The term “B cell proliferative disorder” or “B cell malignancy” refers to a disorder that is associated with some degree of abnormal B cell proliferation and includes, for example, a lymphoma, leukemia, myeloma, and myelodysplastic syndrome. In one embodiment, the B cell proliferative disorder is a myeloma, such as multiple myeloma (MM).

“Effector functions” refer to those biological activities attributable to the Fc region of an antibody, which vary with the antibody isotype. Examples of antibody effector functions include: C1q binding and complement dependent cytotoxicity (CDC); Fc receptor binding; antibody-dependent cell- mediated cytotoxicity (ADCC); phagocytosis; down regulation of cell surface receptors (e.g., B cell receptor); and B cell activation.

“Complement dependent cytotoxicity” or “CDC” refers to the lysis of a target cell in the presence of complement. Activation of the classical complement pathway is initiated by the binding of the first component of the complement system (C1q) to antibodies (of the appropriate subclass) that are bound to their cognate antigen. To assess complement activation, a CDC assay, e.g., as described in Gazzano-Santoro et al., J. Immunol. Methods 202:163 (1996), can be performed.

“Antibody-dependent cell-mediated cytotoxicity” or “ADCC” refers to a form of cytotoxicity in which secreted Ig bound onto Fc receptors (FcRs) present on certain cytotoxic cells {e.g., Natural Killer (NK) cells, neutrophils, and macrophages) enable these cytotoxic effector cells to bind specifically to an antigen-bearing target cell and subsequently kill the target cell with cytotoxic agents. The antibodies “arm” the cytotoxic cells and are absolutely required for such killing. The primary cells for mediating ADCC, NK cells, express FcyRIII only, whereas monocytes express FcyRI, FcyRII, and FcyRIII. FcR expression on hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet. Anna. Rev. Immunol. 9:457-92, 1991 . To assess ADCC activity of a molecule of interest, an in vitro ADCC assay, such as that described in U.S. Patent No. 5,500,362 or 5,821 ,337 can be performed. Useful effector cells for such assays include peripheral blood mononuclear cells (PBMC) and Natural Killer (NK) cells. Alternatively, or additionally, ADCC activity of the molecule of interest can be assessed in vivo, e.g., in an animal model such as that disclosed in Clynes et al. Proc. Natl. Acad. Sci. USA. 95:652-656, 1998.

“Complex” or “complexed” as used herein refers to the association of two or more molecules that interact with each other through bonds and/or forces {e.g., Van der Waals, hydrophobic, hydrophilic forces) that are not peptide bonds. In one aspect, the complex is heteromultimeric. It should be understood that the term “protein complex” or “polypeptide complex” as used herein includes complexes that have a non-protein entity conjugated to a protein in the protein complex (e.g., including, but not limited to, chemical molecules such as a toxin or a detection agent).

As used herein, “delaying progression” of a disorder or disease means to defer, hinder, slow, retard, stabilize, and/or postpone development of the disease or disorder (e.g., a cell proliferative disorder, e.g., cancer). This delay can be of varying lengths of time, depending on the history of the disease and/or individual being treated. As is evident to one skilled in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop the disease. For example, a late stage cancer, such as development of metastasis, may be delayed.

An “effective amount” of a compound, for example, an anti-FcRH5/anti-CD3 T-cell-dependent bispecific antibody (TDB) described herein or a composition (e.g., pharmaceutical composition) thereof, is at least the minimum amount required to achieve the desired therapeutic or prophylactic result, such as a measurable improvement or prevention of a particular disorder (e.g., a cell proliferative disorder, e.g., cancer). An effective amount herein may vary according to factors such as the disease state, age, sex, and weight of the patient, and the ability of the antibody to elicit a desired response in the individual. An effective amount is also one in which any toxic or detrimental effects of the treatment are outweighed by the therapeutically beneficial effects. For prophylactic use, beneficial or desired results include results such as eliminating or reducing the risk, lessening the severity, or delaying the onset of the disease, including biochemical, histological and/or behavioral symptoms of the disease, its complications, and intermediate pathological phenotypes presenting during development of the disease. For therapeutic use, beneficial or desired results include clinical results such as decreasing one or more symptoms resulting from the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, enhancing effect of another medication such as via targeting, delaying the progression of the disease, and/or prolonging survival. In the case of cancer or tumor, an effective amount of the drug may have the effect in reducing the number of cancer cells; reducing the tumor size; inhibiting (/.e., slow to some extent or desirably stop) cancer cell infiltration into peripheral organs; inhibit (/.e., slow to some extent and desirably stop) tumor metastasis; inhibiting to some extent tumor growth; and/or relieving to some extent one or more of the symptoms associated with the disorder. An effective amount can be administered in one or more administrations. For purposes of this invention, an effective amount of drug, compound, or pharmaceutical composition is an amount sufficient to accomplish prophylactic or therapeutic treatment either directly or indirectly. As is understood in the clinical context, an effective amount of a drug, compound, or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound, or pharmaceutical composition. Thus, an “effective amount” may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable result may be or is achieved.

As used herein, “overall survival” or “OS” refers to the percentage of individuals in a group who are likely to be alive after a particular duration of time. As used herein, “objective response rate” or “ORR” refers to the sum of stringent complete response (sCR), complete response (CR), very good partial response (VGPR), and partial response (PR) rates as determined using the International Myeloma Working Group response criteria (Table 13; Kumar et al., Lancet. Oncol., 17:e328-346, 2019).

The term “epitope” refers to the particular site on an antigen molecule to which an antibody binds. In some aspects, the particular site on an antigen molecule to which an antibody binds is determined by hydroxyl radical footprinting. In some aspects, the particular site on an antigen molecule to which an antibody binds is determined by crystallography.

A “growth inhibitory agent” when used herein refers to a compound or composition which inhibits growth of a cell either in vitro or in vivo. In one aspect, growth inhibitory agent is growth inhibitory antibody that prevents or reduces proliferation of a cell expressing an antigen to which the antibody binds. In another aspect, the growth inhibitory agent may be one which significantly reduces the percentage of cells in S phase. Aspects of growth inhibitory agents include agents that block cell cycle progression (at a place other than S phase), such as agents that induce G1 arrest and M-phase arrest. Classical M-phase blockers include the vincas (vincristine and vinblastine), taxanes, and topoisomerase II inhibitors such as doxorubicin, epirubicin, daunorubicin, etoposide, and bleomycin. Those agents that arrest G1 also spill over into S-phase arrest, for example, DNA alkylating agents such as tamoxifen, prednisone, dacarbazine, mechlorethamine, cisplatin, methotrexate, 5-fluorouracil, and ara-C. Further information can be found in Mendelsohn and Israel, eds., The Molecular Basis of Cancer, Chapter 1 , entitled “Cell cycle regulation, oncogenes, and antineoplastic drugs” by Murakami et al. (W.B. Saunders, Philadelphia, 1995), e.g., p. 13. The taxanes (paclitaxel and docetaxel) are anticancer drugs both derived from the yew tree. Docetaxel (TAXOTERE®, Rhone-Poulenc Rorer), derived from the European yew, is a semisynthetic analogue of paclitaxel (TAXOL®, Bristol-Myers Squibb). Paclitaxel and docetaxel promote the assembly of microtubules from tubulin dimers and stabilize microtubules by preventing depolymerization, which results in the inhibition of mitosis in cells.

An “immunoconjugate” is an antibody conjugated to one or more heterologous molecule(s), including but not limited to a cytotoxic agent.

The term “immunomodulatory agent” refers to a class of molecules that modifies the immune system response or the functioning of the immune system. Immunomodulatory agents include, but are not limited to, PD-1 axis binding antagonists, thalidomide (a-N-phthalimido-glutarimide) and its analogues, OTEZLA® (apremilast), REVLIMID® (lenalidomide) and POMALYST® (pomalidomide), and pharmaceutically acceptable salts or acids thereof.

A “subject” or an “individual” is a mammal. Mammals include, but are not limited to, domesticated animals (e.g., cows, sheep, cats, dogs, and horses), primates (e.g., humans and nonhuman primates such as monkeys), rabbits, and rodents (e.g., mice and rats). In certain aspects, the subject or individual is a human.

An “isolated” protein or peptide is one which has been separated from a component of its natural environment. In some aspects, a protein or peptide is purified to greater than 95% or 99% purity as determined by, for example, electrophoresis (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatography (e.g., ion exchange or reverse phase HPLC).

An “isolated” nucleic acid refers to a nucleic acid molecule that has been separated from a component of its natural environment. An isolated nucleic acid includes a nucleic acid molecule contained in cells that ordinarily contain the nucleic acid molecule, but the nucleic acid molecule is present extrachromosomally or at a chromosomal location that is different from its natural chromosomal location.

The term “PD-1 axis binding antagonist” refers to a molecule that inhibits the interaction of a PD-1 axis binding partner with either one or more of its binding partners, so as to remove T-cell dysfunction resulting from signaling on the PD-1 signaling axis, with a result being to restore or enhance T-cell function (e.g., proliferation, cytokine production, and/or target cell killing). As used herein, a PD-1 axis binding antagonist includes a PD-L1 binding antagonist, a PD-1 binding antagonist, and a PD-L2 binding antagonist. In some instances, the PD-1 axis binding antagonist includes a PD-L1 binding antagonist or a PD-1 binding antagonist. In a preferred aspect, the PD-1 axis binding antagonist is a PD-L1 binding antagonist.

The term “PD-L1 binding antagonist” refers to a molecule that decreases, blocks, inhibits, abrogates, or interferes with signal transduction resulting from the interaction of PD-L1 with either one or more of its binding partners, such as PD-1 and/or B7-1 . In some instances, a PD-L1 binding antagonist is a molecule that inhibits the binding of PD-L1 to its binding partners. In a specific aspect, the PD-L1 binding antagonist inhibits binding of PD-L1 to PD-1 and/or B7-1 . In some instances, the PD-L1 binding antagonists include anti-PD-L1 antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides and other molecules that decrease, block, inhibit, abrogate or interfere with signal transduction resulting from the interaction of PD-L1 with one or more of its binding partners, such as PD-1 and/or B7-1 . In one instance, a PD-L1 binding antagonist reduces the negative co-stimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes mediated signaling through PD-L1 so as to render a dysfunctional T-cell less dysfunctional (e.g., enhancing effector responses to antigen recognition). In some instances, the PD- L1 binding antagonist binds to PD-L1 . In some instances, a PD-L1 binding antagonist is an anti-PD-L1 antibody (e.g., an anti-PD-L1 antagonist antibody). Exemplary anti-PD-L1 antagonist antibodies include atezolizumab, MDX-1 105, MEDI4736 (durvalumab), MSB0010718C (avelumab), SHR-1316, CS1001 , envafolimab, TQB2450, ZKAB001 , LP-002, CX-072, IMC-001 , KL-A167, APL-502, cosibelimab, lodapolimab, FAZ053, TG-1501 , BGB-A333, BCD-135, AK-106, LDP, GR1405, HLX20, MSB231 1 , RC98, PDL-GEX, KD036, KY1003, YBL-007, and HS-636. In some aspects, the anti-PD- L1 antibody is atezolizumab, MDX-1 105, MEDI4736 (durvalumab), or MSB0010718C (avelumab). In one specific aspect, the PD-L1 binding antagonist is MDX-1 105. In another specific aspect, the PD-L1 binding antagonist is MEDI4736 (durvalumab). In another specific aspect, the PD-L1 binding antagonist is MSB0010718C (avelumab). In other aspects, the PD-L1 binding antagonist may be a small molecule, e.g., GS-4224, INCB086550, MAX-10181 , INCB090244, CA-170, or ABSK041 , which in some instances may be administered orally. Other exemplary PD-L1 binding antagonists include AVA-004, MT-6035, VXM10, LYN192, GB7003, and JS-003. In a preferred aspect, the PD-L1 binding antagonist is atezolizumab.

The term “PD-1 binding antagonist” refers to a molecule that decreases, blocks, inhibits, abrogates or interferes with signal transduction resulting from the interaction of PD-1 with one or more of its binding partners, such as PD-L1 and/or PD-L2. PD-1 (programmed death 1 ) is also referred to in the art as “programmed cell death 1 ,” “PDCD1 ,” “CD279,” and “SLEB2.” An exemplary human PD-1 is shown in UniProtKB/Swiss-Prot Accession No. Q15116. In some instances, the PD-1 binding antagonist is a molecule that inhibits the binding of PD-1 to one or more of its binding partners. In a specific aspect, the PD-1 binding antagonist inhibits the binding of PD-1 to PD-L1 and/or PD-L2. For example, PD-1 binding antagonists include anti-PD-1 antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides, and other molecules that decrease, block, inhibit, abrogate or interfere with signal transduction resulting from the interaction of PD-1 with PD-L1 and/or PD-L2. In one instance, a PD-1 binding antagonist reduces the negative co-stimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes mediated signaling through PD-1 so as render a dysfunctional T-cell less dysfunctional (e.g., enhancing effector responses to antigen recognition). In some instances, the PD-1 binding antagonist binds to PD-1 . In some instances, the PD-1 binding antagonist is an anti-PD-1 antibody (e.g., an anti-PD-1 antagonist antibody). Exemplary anti-PD-1 antagonist antibodies include nivolumab, pembrolizumab, MEDI- 0680, PDR001 (spartalizumab), REGN2810 (cemiplimab), BGB-108, prolgolimab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostarlimab, retifanlimab, sasanlimab, penpulimab, CS1003, HLX10, SCT-I10A, zimberelimab, balstilimab, genolimzumab, Bl 754091 , cetrelimab, YBL-006, BAT1306, HX008, budigalimab, AMG 404, CX-188, JTX-4014, 609A, Sym021 , LZM009, F520, SG001 , AM0001 , ENUM 244C8, ENUM 388D4, STI-1110, AK-103, and hAb21 . In a specific aspect, a PD-1 binding antagonist is MDX-1106 (nivolumab). In another specific aspect, a PD-1 binding antagonist is MK-3475 (pembrolizumab). In another specific aspect, a PD-1 binding antagonist is a PD-L2 Fc fusion protein, e.g., AMP-224. In another specific aspect, a PD-1 binding antagonist is MED1 -0680. In another specific aspect, a PD-1 binding antagonist is PDR001 (spartalizumab). In another specific aspect, a PD-1 binding antagonist is REGN2810 (cemiplimab). In another specific aspect, a PD-1 binding antagonist is BGB-108. In another specific aspect, a PD-1 binding antagonist is prolgolimab. In another specific aspect, a PD-1 binding antagonist is camrelizumab. In another specific aspect, a PD-1 binding antagonist is sintilimab. In another specific aspect, a PD-1 binding antagonist is tislelizumab. In another specific aspect, a PD-1 binding antagonist is toripalimab. Other additional exemplary PD-1 binding antagonists include BION-004, CB201 , AUNP-012, ADG104, and LBL-006.

The term “PD-L2 binding antagonist” refers to a molecule that decreases, blocks, inhibits, abrogates or interferes with signal transduction resulting from the interaction of PD-L2 with either one or more of its binding partners, such as PD-1 . PD-L2 (programmed death ligand 2) is also referred to in the art as “programmed cell death 1 ligand 2,” “PDCD1 LG2,” “CD273,” “B7-DC,” “Btdc,” and “PDL2.” An exemplary human PD-L2 is shown in UniProtKB/Swiss-Prot Accession No. Q9BQ51 . In some instances, a PD-L2 binding antagonist is a molecule that inhibits the binding of PD-L2 to one or more of its binding partners. In a specific aspect, the PD-L2 binding antagonist inhibits binding of PD- L2 to PD-1 . Exemplary PD-L2 antagonists include anti-PD-L2 antibodies, antigen binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides and other molecules that decrease, block, inhibit, abrogate or interfere with signal transduction resulting from the interaction of PD-L2 with either one or more of its binding partners, such as PD-1 . In one aspect, a PD-L2 binding antagonist reduces the negative co-stimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes mediated signaling through PD-L2 so as render a dysfunctional T-cell less dysfunctional (e.g., enhancing effector responses to antigen recognition). In some aspects, the PD-L2 binding antagonist binds to PD-L2. In some aspects, a PD-L2 binding antagonist is an immunoadhesin. In other aspects, a PD-L2 binding antagonist is an anti-PD-L2 antagonist antibody.

The term “protein,” as used herein, refers to any native protein from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated. The term encompasses “full-length,” unprocessed protein as well as any form of the protein that results from processing in the cell. The term also encompasses naturally occurring variants of the protein, e.g., splice variants or allelic variants.

“Percent (%) amino acid sequence identity” with respect to a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the reference polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximal alignment over the full-length of the sequences being compared. For purposes herein, however, % amino acid sequence identity values are generated using the sequence comparison computer program ALIGN-2. The ALIGN-2 sequence comparison computer program was authored by Genentech, Inc., and the source code has been filed with user documentation in the U.S. Copyright Office, Washington D.C., 20559, where it is registered under U.S. Copyright Registration No. TXU510087. The ALIGN-2 program is publicly available from Genentech, Inc., South San Francisco, California, or may be compiled from the source code. The ALIGN-2 program should be compiled for use on a UNIX operating system, including digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and do not vary.

In situations where ALIGN-2 is employed for amino acid sequence comparisons, the % amino acid sequence identity of a given amino acid sequence A to, with, or against a given amino acid sequence B (which can alternatively be phrased as a given amino acid sequence A that has or comprises a certain % amino acid sequence identity to, with, or against a given amino acid sequence B) is calculated as follows: 100 times the fraction X/Y where X is the number of amino acid residues scored as identical matches by the sequence alignment program ALIGN-2 in that program’s alignment of A and B, and where Y is the total number of amino acid residues in B. It will be appreciated that where the length of amino acid sequence A is not equal to the length of amino acid sequence B, the % amino acid sequence identity of A to B will not equal the % amino acid sequence identity of B to A. Unless specifically stated otherwise, all % amino acid sequence identity values used herein are obtained as described in the immediately preceding paragraph using the ALIGN-2 computer program.

The term “pharmaceutical formulation” refers to a preparation which is in such form as to permit the biological activity of an active ingredient contained therein to be effective, and which contains no additional components which are unacceptably toxic to a subject to which the formulation would be administered.

A “pharmaceutically acceptable carrier” refers to an ingredient in a pharmaceutical formulation, other than an active ingredient, which is nontoxic to a subject. A pharmaceutically acceptable carrier includes, but is not limited to, a buffer, excipient, stabilizer, or preservative.

By “radiation therapy” is meant the use of directed gamma rays or beta rays to induce sufficient damage to a cell so as to limit its ability to function normally or to destroy the cell altogether. It will be appreciated that there will be many ways known in the art to determine the dosage and duration of treatment. Typical treatments are given as a one-time administration and typical dosages range from 10 to 200 units (Grays) per day.

As used herein, “treatment” (and grammatical variations thereof such as “treat” or “treating”) refers to clinical intervention in an attempt to alter the natural course of the individual being treated, and can be performed either for prophylaxis or during the course of clinical pathology. Desirable effects of treatment include, but are not limited to, preventing occurrence or recurrence of disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, preventing metastasis, decreasing the rate of disease progression, amelioration or palliation of the disease state, and remission or improved prognosis. In some aspects, antibodies described herein (e.g., an anti-FcRH5/anti-CD3 bispecific antibody) are used to delay development of a disease or to slow the progression of a disease.

By “reduce” or “inhibit” is meant the ability to cause an overall decrease, for example, of 20% or greater, of 50% or greater, or of 75%, 85%, 90%, 95%, or greater. In certain aspects, reduce or inhibit can refer to the effector function of an antibody that is mediated by the antibody Fc region, such effector functions specifically including complement-dependent cytotoxicity (CDC), antibodydependent cellular cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP).

According to the invention, the term "vaccine" relates to a pharmaceutical preparation (pharmaceutical composition) or product that upon administration induces an immune response, in particular a cellular immune response, which recognizes and attacks a pathogen or a diseased cell such as a cancer cell. A vaccine may be used for the prevention or treatment of a disease. A vaccine may be a cancer vaccine. A “cancer vaccine” as used herein is a composition that stimulates an immune response in a subject against a cancer. Cancer vaccines typically consist of a source of cancer-associated material or cells (antigen) that may be autologous (from self) or allogenic (from others) to the subject, along with other components (e.g., adjuvants) to further stimulate and boost the immune response against the antigen. Cancer vaccines can result in stimulating the immune system of the subject to produce antibodies to one or several specific antigens, and/or to produce killer T cells to attack cancer cells that have those antigens.

As used herein, “administering” is meant a method of giving a dosage of a compound (e.g., an anti-FcRH5/anti-CD3 bispecific antibody) to a subject. In some aspects, the compositions utilized in the methods herein are administered intravenously. The compositions utilized in the methods described herein can be administered, for example, intramuscularly, intravenously, intradermally, percutaneously, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostatically, intrapleurally, intratracheally, intranasally, intravitreally, intravaginally, intrarectally, topically, intratumorally, peritoneally, subcutaneously, subconjunctivally, intravesicularlly, mucosally, intrapericardially, intraumbilically, intraocularly, orally, topically, locally, by inhalation, by injection, by infusion, by continuous infusion, by localized perfusion bathing target cells directly, by catheter, by lavage, in cremes, or in lipid compositions. The method of administration can vary depending on various factors (e.g., the compound or composition being administered and the severity of the condition, disease, or disorder being treated).

“CD38” as used herein refers to a CD38 glycoprotein found on the surface of many immune cells, including CD4+, CD8+, B lymphocytes, and natural killer (NK) cells, and includes any native CD38 from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated. CD38 is expressed at a higher level and more uniformly on myeloma cells as compared to normal lymphoid and myeloid cells. The term encompasses “full-length,” unprocessed CD38, as well as any form of CD38 that results from processing in the cell. The term also encompasses naturally occurring variants of CD38, e.g., splice variants or allelic variants. CD38 is also referred to in the art as cluster of differentiation 38, ADP- ribosyl cyclase 1 , cADPr hydrolase 1 , and cyclic ADP-ribose hydrolase 1 . CD38 is encoded by the CD38 gene. The nucleic acid sequence of an exemplary human CD38 is shown under NCBI Reference Sequence: NM_001775.4 or in SEQ ID NO: 33. The amino acid sequence of an exemplary human CD38 protein encoded by CD38 is shown under UniProt Accession No. P28907 or in SEQ ID NO: 34.

The term “anti-CD38 antibody” encompasses all antibodies that bind CD38 with sufficient affinity such that the antibody is useful as a therapeutic agent in targeting a cell expressing the antigen, and does not significantly cross-react with other proteins such as a negative control protein in the assays described below. For example, an anti-CD38 antibody may bind to CD38 on the surface of a MM cell and mediate cell lysis through the activation of complement-dependent cytotoxicity, ADCC, antibody-dependent cellular phagocytosis (ADCP), and apoptosis mediated by Fc cross-linking, leading to the depletion of malignant cells and reduction of the overall cancer burden. An anti-CD38 antibody may also modulate CD38 enzyme activity through inhibition of ribosyl cyclase enzyme activity and stimulation of the cyclic adenosine diphosphate ribose (cADPR) hydrolase activity of CD38. In certain aspects, an anti-CD38 antibody that binds to CD38 has a dissociation constant (KD) of < 1 pM, < 100 nM, < 10 nM, < 1 nM, < 0.1 nM, < 0.01 nM, or < 0.001 nM (e.g., 10⁸ M or less, e.g., from 10^-8 M to 10^-13 M, e.g., from 10^-9 M to 10^-13 M). In certain aspects, the anti-CD38 antibody may bind to both human CD38 and chimpanzee CD38. Anti-CD38 antibodies also include anti-CD38 antagonist antibodies. Bispecific antibodies wherein one arm of the antibody binds CD38 are also contemplated. Also encompassed by this definition of anti-CD38 antibody are functional fragments of the preceding antibodies. Examples of antibodies which bind CD38 include: daratumumab (DARZALEX®) (U.S. Patent No: 7,829,673 and U.S. Pub. No: 20160067205 A1 ); “MOR202” (U.S. Patent No: 8,263,746); and isatuximab (SAR-650984).

As used herein, the term “relative increase” refers to an increase in the survival (e.g., as measured by progression-free survival (PFS) or overall survival (OS)) of a subject having MM and whose baseline sample has been determined to have a decreased level of one or more cell types set forth in Table 3, an increased level of one or more cell types set forth in Table 4, a lower number in one or more of the features set forth in Table 5, a decreased level of one or more cell types set forth in Table 6, an increased level of one or more cell types set forth in Table 7, a decreased level of one or more cell types set forth in Table 8, or an increased level of one or more cell types set forth in Table 9 relative to a subject having an MM and whose baseline sample has been determined to have an increased level of one or more cell types set forth in Table 3, a decreased level of one or more cell types set forth in Table 4, a higher number in one or more of the features set forth in Table 5, an increased level of one or more cell types set forth in Table 6, a decreased level of one or more cell types set forth in Table 7, an increased level of one or more cell types set forth in Table 8, or a decreased level of one or more cell types set forth in Table 9.

As used herein, the term “reference level” refers to a mean or median level (e.g., percentage, fold change, Z-score, and the like), mode, quartile level, or pre-assigned value/level of a given cell type in a population of subjects have an MM. Exemplary reference levels for a plurality of cell types described herein (e.g., cell types in Table 1 , Table 2, Table 3, Table 4, Table 6, Table 7, Table 8, or Table 9) are provided in Table 14.

As used herein, the term “reference number” refers to a mean or median number, mode, quartile, or pre-assigned value of a given feature set forth in Table 5 in a population of subjects having an MM. Exemplary reference numbers for a given feature described herein (e.g., features in Table 5) are provided in Table 15.

As used herein, the term “a population of subjects have an MM” refers to an MM patient population that is at least 10 subjects in size (e.g., at least 10, at least 15, at least 20, at least 25, at least 50, at least 75, at least 100, at least 125, at least 150, at least 175, at least 200, at least 225, at least 228, at least 250, at least 275, at least 300, at least 325, at least 350, at least 375, at least 400, at least 425, at least 450, at least 475, at least 500, at least 525, at least 550, at least 575, at least 600, at least 625, at least 650, at least 675, at least 700, at least 725, at least 750, at least 775, at least 800, at least 825, at least 850, at least 875, at least 900, at least 925, at least 950, at least 975, at least 1000, or more in size). For example, a population of subjects having an MM can refer to an MM patient population that is 228 subjects in size.

II. THERAPEUTIC METHODS

The present invention provides methods useful for treating subjects having MM who would benefit from treatment with a bispecific antibody that binds to fragment crystallizable receptor-like 5 (FcRH5)/anti-cluster of differentiation 3 (CD3).

As described below, (i) measuring or determining a level of one or more cell types set forth in Table 3, Table 4, Table 6, Table 7, Table 8, and/or Table 9 in a sample from the subject or (ii) a number in one or more of the features of the subject set forth in Table 5 can be useful for identifying subjects having MM who would benefit from treatment with a bispecific antibody that binds to fragment crystallizable receptor-like 5 (FcRH5)/anti-cluster of differentiation 3 (CD3).

The methods described herein may require determining a level of a T cell (e.g., a CD4+ or CD8+ T cell), a T naive (TN) cell, a T central memory (TCM) cell, T effector memory (TEM) cell, a terminally differentiated effector memory (TEMRA) cell, a natural Killer (NK) cell, a natural killer T cell (NKT cell), a T regulatory (Treg) cell, a white blood cell (WBC), a non-lymphoid cell (e.g., a CD3- cell), or any combination thereof.

A TN cell is a mature T cell in circulation that has never encountered nor responded to its cognate antigen, thereby distinguishing said T cell from effector and memory T cell subtypes. Upon activation, naive CD8+ T cells may differentiate into cytotoxic T cells, and naive CD4+ T cells may differentiate into T helper cells (e.g., TH1 or TH2 cells). A TCM cell is a memory T cell largely restricted to lymphoid organs and the blood that provides immunosurveillance due to its high sensitivity and rapid response to its cognate antigen exposure. A TEM cell is a memory T cell largely found in peripheral circulation and tissues rather than lymphoid organs. TEM cells are long lasting and may quickly proliferate into large numbers upon re-exposure to its cognate antigen. A TEMRA cell plays an important role in humoral and cellular rejection. TEMRA cells generally have a shortened lifespan and carries higher levels of cytotoxic and exhausted genes compared to other effector or memory cells. A NK cell is a large, granular lymphocyte that mediates innate immunity to tumors and pathogens, as well as mediates antibody-dependent cell-mediated cytotoxicity (ADCC). A Treg cell dampens or suppresses an immune response by secreting anti-inflammatory cytokines. Its role in immune suppression maintains peripheral tolerance and aids in preventing autoimmune or inflammatory diseases or conditions. Exemplary positive and negative markers useful for identifying these cell types are described in Table 2. Table 2. Exemplary Cell Markers for Cell Identification

TN = T naive; TCM = T central memory; TEM = T effector memory; TEMRA = terminally differentiated effector memory; Treg = T regulatory; NK = natural killer; NKT = natural killer T cells; CD8 = cluster of differentiation 8; CD4 = cluster of differentiation 4; CD16 = Cluster of differentiation 16; CD19 = Cluster of differentiation 19; CD56 = Cluster of differentiation 56; CD45RA = Cluster of differentiation RA45; CD45RO = Cluster of differentiation 45RO; GzB= Granzyme B; CCR7 = c-c chemokine receptor type 7

Cell types associated with increased resistance to cevostamab

In some aspects of the invention, the methods described herein require determining a level of one or more cell types set forth in Table 3 in the subject. In some aspects of the invention, the methods described herein require that a level of one or more cell types set forth in Table 3 has been previously determined in the subject.

In general, MM subjects having an increased level (e.g., presence or percentage) of one or more (e.g., one, two, three, four, five, six, seven, eight, nine, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20,

21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47,

48, 49, 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 , 72, 73, 74,

75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, or all 85) cell types set forth in Table 3 in a sample (e.g., a baseline sample), as compared to a reference level, are more resistant to treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab). For example, a level of a cell type in Table 3 may be increased in a sample from the subject by about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21 %, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41 %, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61 %, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91 %, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 101 %, about 102%, about 103%, about 104%, about 105%, about 106%, about 107%, about 108%, about 109%, about 1 10%, about 1 1 1 %, about 1 12%, about 1 13%, about 1 14%, about 1 15%, about 1 16%, about 1 17%, about 1 18%, about 1 19%, about 120%, about 121 %, about 122%, about 123%, about 124%, about 125%, about 126%, about 127%, about 128%, about 129%, about 130%, about 131 %, about 132%, about 133%, about 134%, about 135%, about 136%, about 137%, about 138%, about 139%, about 140%, about 141 %, about 142%, about 143%, about 144%, about 145%, about 146%, about 147%, about 148%, about 149%, about 150%, about 151 %, about 152%, about 153%, about 154%, about 155%, about 156%, about 157%, about 158%, about 159%, about 160%, about 161 %, about 162%, about 163%, about 164%, about 165%, about 166%, about 167%, about 168%, about 169%, about

170%, about 171 %, about 172%, about 173%, about 174%, about 175%, about 176%, about 177%, about 178%, about 179%, about 180%, about 181 %, about 182%, about 183%, about 184%, about

185%, about 186%, about 187%, about 188%, about 189%, about 190%, about 191 %, about 192%, about 193%, about 194%, about 195%, about 196%, about 197%, about 198%, about 199%, or about

200%, as compared to a reference level, thereby indicating that the subject is unlikely to benefit from treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab).

Table 3. Cell Types Associated with Increased Resistance to Cevostamab

CD = cluster of differentiation; DR = human leukocyte antigen - DR isotype; Ki67 = antigen Kiel 67; PD1 = programmed cell death protein 1 ; GzB = Granzyme B; TIGIT = T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains; TIM3 = T cell immunoglobulin and mucin-domain containing-3; TN cells = naive T cells; TCM cells = central memory T cells; TEM cells = effector memory T cells; TEMRA cells = terminally differentiated effector memory T cells; Treg cells = regulatory T cells; NK cells = natural killer cells

Conversely, MM subjects having a decreased level (e.g., presence or percentage) of one or more (e.g., one, two, three, four, five, six, seven, eight, nine, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20,

75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, or all 85) cell types set forth in Table 3 in a sample (e.g., a baseline sample), as compared to a reference level, are generally more sensitive to treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab). For example, a level of a cell type in Table 3 may be decreased in a sample from the subject by about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41 %, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51 %, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91 %, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%, as compared to a reference level, thereby indicating that the subject would likely benefit from treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab).

Cell types associated with increased sensitivity to cevostamab

In some aspects of the invention, the methods described herein require determining a level of one or more cell types set forth in Table 4 in the subject. In some aspects of the invention, the methods described herein require that a level of one or more cell types set forth in Table 4 has been previously determined in the subject.

In general, MM subjects having an increased level (e.g., presence or percentage) of one or more (e.g., one, two, three, four, five, six, seven, or all eight) cell types set forth in Table 4 in a sample (e.g., a baseline sample), as compared to a reference level, are more sensitive to treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab). For example, a level of a cell type in Table 4 may be increased in a sample from the subject by about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21 %, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51 %, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61 %, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91 %, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 101%, about 102%, about 103%, about 104%, about 105%, about 106%, about 107%, about 108%, about 109%, about 110%, about 111 %, about 112%, about 113%, about 114%, about 115%, about 116%, about 117%, about 118%, about 119%, about 120%, about 121 %, about 122%, about 123%, about 124%, about 125%, about 126%, about 127%, about 128%, about 129%, about 130%, about 131%, about 132%, about 133%, about 134%, about 135%, about 136%, about 137%, about 138%, about 139%, about 140%, about 141 %, about 142%, about 143%, about 144%, about 145%, about 146%, about 147%, about 148%, about 149%, about 150%, about 151%, about 152%, about 153%, about 154%, about 155%, about 156%, about 157%, about 158%, about 159%, about 160%, about 161%, about 162%, about 163%, about 164%, about 165%, about 166%, about 167%, about 168%, about 169%, about 170%, about 171%, about 172%, about 173%, about 174%, about 175%, about 176%, about 177%, about 178%, about 179%, about 180%, about 181%, about 182%, about 183%, about 184%, about 185%, about 186%, about 187%, about 188%, about 189%, about 190%, about 191%, about 192%, about 193%, about 194%, about 195%, about 196%, about 197%, about 198%, about 199%, or about 200%, as compared to a reference level, thereby indicating that the subject would likely benefit from treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab).

Table 4. Cell Types Associated with Increased Sensitivity to Cevostamab

CD = cluster of differentiation; NK T cells = natural killer T cells; TN cells = naive T cells; TCM cells = central memory T cells; NK cells = natural killer cells

Conversely, MM subjects having a decreased level (e.g., presence or percentage) of one or more (e.g., one, two, three, four, five, six, seven, or all eight) cell types set forth in Table 4 in a sample (e.g., a baseline sample), as compared to a reference level, are generally more resistant to treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab). For example, a level of a cell type in Table 4 may be decreased in a sample from the subject by about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11 %, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21 %, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51 %, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61 %, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91 %, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%, as compared to a reference level, thereby indicating that the subject is unlikely to benefit from treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab).

Subject features associated with increased resistance to cevostamab

In some aspects of the invention, the methods described herein require determining one or more features set forth in Table 5 in the subject. In some aspects of the invention, the methods described herein require that one or more of the features set forth in Table 5 has been previously determined in the subject.

In general, MM subjects having a higher number in one or more (e.g., one, two, three, four, five, six, seven, eight, nine, 10, 11 , 12, 13, or all 14) features set forth in Table 5, as compared to a reference number, are more resistant to treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab). For example, a number in one or more features in Table 5 may be higher by one, two, three, four, five, six, seven, eight, nine, 10, 11 , 12, 13, 14, or 15, as compared to a reference number, thereby indicating that the subject is unlikely to benefit from treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab). Table 5. Subject Features Associated with Resistance to Cevostamab

Pl= proteasome inhibitor; IMID= immunomodulatory drugs; BCMA= B cell maturation antigen; CD= cluster of differentiation; CAR-T= chimeric antigen receptor T cell

Conversely, MM subjects having a lower number in one or more (e.g., one, two, three, four, five, six, seven, eight, nine, 10, 11 , 12, 13, or all 14) features set forth in Table 5, as compared to a reference number, are generally more sensitive to treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab). For example, a number in one or more features in Table 5 may be lowered by one, two, three, four, five, six, seven, eight, nine, 10, 11 , 12, 13, 14, or 15, as compared to a reference number, thereby indicating that the subject would likely benefit from treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab).

Cell types in bone marrow that are associated with increased resistance to cevostamab In some aspects of the invention, the methods described herein require determining a level of one or more cell types set forth in Table 6 in the bone marrow of the subject. In some aspects of the invention, the methods described herein require that a level of one or more cell types set forth in Table 6 has been previously determined in the bone marrow of the subject.

In general, MM subjects having an increased level (e.g., presence or percentage) of one or more (e.g., one, two, three, four, five, six, seven, eight, nine, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, or all 69) cell types set forth in Table 6 in a bone marrow sample (e.g., a baseline bone marrow sample), as compared to a reference level, are more resistant to treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab). For example, in some embodiments, a level of CD4+CD25-CD69+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 27% to about 80% (e.g., about 27% to about 54%, about 40% to about 60%, or about 54% to about 80%), as compared to a reference level. In some embodiments, a level of CD4+DR+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 15% to about 44% (e.g., about 15% to about 29%, about 22% to about 33%, or about 29% to about 44%), as compared to a reference level. In some embodiments, a level of CD4+DR+GzB+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 17% to about 52% (e.g., about 17% to about 34%, about 26% to about 39%, or about 34% to about 52%), as compared to a reference level. In some embodiments, a level of CD4+DR+KI67+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 28% to about 83% (e.g., about 28% to about 55%, about 42% to about 62%, or about 55% to about 83%), as compared to a reference level. In some embodiments, a level of CD4+DR+PD1 + T cells in a sample (e.g., bone marrow) from the subject is increased by about 26% to about 77% (e.g., about 26% to about 51 %, about 38% to about 58%, or about 51 % to about 77%), as compared to a reference level. In some embodiments, a level of CD4+KI67+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 23% to about 68% (e.g., about 23% to about 46%, about 34% to about 51 %, or about 46% to about 68%), as compared to a reference level. In some embodiments, a level of CD4+PD1 + T cells in a sample (e.g., bone marrow) from the subject is increased by about 13% to about 40% (e.g., about 13% to about 27%, about 20% to about 30%, or about 27% to about 40%), as compared to a reference level. In some embodiments, a level of CD4+PD1 + T cells in a sample (e.g., bone marrow) from the subject is increased by about 15% to about 45% (e.g., about 15% to about 30%, about 22% to about 34%, or about 30% to about 45%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +GzB+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 18% to about 55% (e.g., about 18% to about 36%, about 27% to about 41 %, or about 36% to about 55%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +KI67+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 30% to about 89% (e.g., about 30% to about 59%, about 45% to about 67%, or about 59% to about 89%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +OX40- T cells in a sample (e.g., bone marrow) from the subject is increased by about 12% to about 36% (e.g., about 12% to about 24%, about 18% to about 27%, or about 24% to about 36%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +OX40+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 1 1 % to about 34% (e.g., about 1 1 % to about 23%, about 17% to about 26%, or about 23% to about 34%), as compared to a reference level. In some embodiments, a level of CD4+PD1 -TIGIT+TIM3- T cells in a sample (e.g., bone marrow) from the subject is increased by about 9% to about 26% (e.g., about 9% to about 17%, about 13% to about 19%, or about 17% to about 26%), as compared to a reference level. In some embodiments, a level of CD4+TIGIT+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 10% to about 31 % (e.g., about 10% to about 21 %, about 16% to about 23%, or about 21 % to about 31 %), as compared to a reference level. In some embodiments, a level of CD4+DR+ TCM cells in a sample (e.g., bone marrow) from the subject is increased by about 23% to about 70% (e.g., about 23% to about 47%, about 35% to about 53%, or about 47% to about 70%), as compared to a reference level. In some embodiments, a level of CD4+DR+KI67+ TCM cells in a sample (e.g., bone marrow) from the subject is increased by about 30% to about 91 % (e.g., about 30% to about 61 %, about 46% to about 68%, or about 61 % to about 91 %), as compared to a reference level. In some embodiments, a level of CD4+DR+PD1 + TCM cells in a sample (e.g., bone marrow) from the subject is increased by about 35% to about 104% (e.g., about 35% to about 70%, about 52% to about 78%, or about 70% to about 104%), as compared to a reference level. In some embodiments, a level of CD4+KI67+ TCM cells in a sample (e.g., bone marrow) from the subject is increased by about 23% to about 68% (e.g., about 23% to about 45%, about 34% to about 51 %, or about 45% to about 68%), as compared to a reference level. In some embodiments, a level of CD4+PD1 + TCM cells in a sample (e.g., bone marrow) from the subject is increased by about 17% to about 51 % (e.g., about 17% to about 34%, about 26% to about 39%, or about 34% to about 51 %), as compared to a reference level. In some embodiments, a level of CD4+PD1 +0X40+ TCM cells in a sample (e.g., bone marrow) from the subject is increased by about 14% to about 42% (e.g., about 14% to about 28%, about 21 % to about 31 %, or about 28% to about 42%), as compared to a reference level. In some embodiments, a level of CD4+DR+ TEM cells in a sample (e.g., bone marrow) from the subject is increased by about 10% to about 31 % (e.g., about 10% to about 20%, about 15% to about 23%, or about 20% to about 31 %), as compared to a reference level. In some embodiments, a level of CD4+DR+KI67+ TEM cells in a sample (e.g., bone marrow) from the subject is increased by about 20% to about 59% (e.g., about 20% to about 39%, about 30% to about 44%, or about 39% to about 59%), as compared to a reference level. In some embodiments, a level of CD4+DR+PD1 + TEM cells in a sample (e.g., bone marrow) from the subject is increased by about 17% to about 52% (e.g., about 17% to about 35%, about 26% to about 39%, or about 35% to about 52%), as compared to a reference level. In some embodiments, a level of CD4+KI67+ TEM cells in a sample (e.g., bone marrow) from the subject is increased by about 17% to about 52% (e.g., about 17% to about 34%, about 26% to about 39%, or about 34% to about 52%), as compared to a reference level. In some embodiments, a level of CD4+PD1 + TEM cells in a sample (e.g., bone marrow) from the subject is increased by about 9% to about 27% (e.g., about 9% to about 18%, about 14% to about 21 %, or about 18% to about 27%), as compared to a reference level. In some embodiments, a level of CD4+ TEM cells in a sample (e.g., bone marrow) from the subject is increased by about 6% to about 19% (e.g., about 6% to about 12%, about 9% to about 14%, or about 12% to about 19%), as compared to a reference level. In some embodiments, a level of CD4+ TEM cells in a sample (e.g., bone marrow) from the subject is increased by about 6% to about 18% (e.g., about 6% to about 12%, about 9% to about 14%, or about 12% to about 18%), as compared to a reference level. In some embodiments, a level of CD4+DR+ TEMRA cells in a sample (e.g., bone marrow) from the subject is increased by about 10% to about 29% (e.g., about 10% to about 20%, about 15% to about 22%, or about 20% to about 29%), as compared to a reference level. In some embodiments, a level of CD4+DR+GzB+ TEMRA cells in a sample (e.g., bone marrow) from the subject is increased by about 1 1 % to about 32% (e.g., about 1 1 % to about 21 %, about 16% to about 24%, or about 21 % to about 32%), as compared to a reference level. In some embodiments, a level of CD4+DR+KI67+ TEMRA cells in a sample (e.g., bone marrow) from the subject is increased by about 19% to about 56% (e.g., about 19% to about 38%, about 28% to about 42%, or about 38% to about 56%), as compared to a reference level. In some embodiments, a level of CD4+DR+PD1 + TEMRA cells in a sample (e.g., bone marrow) from the subject is increased by about 17% to about 52% (e.g., about 17% to about 34%, about 26% to about 39%, or about 34% to about 52%), as compared to a reference level. In some embodiments, a level of CD4+KI67+ TEMRA cells in a sample (e.g., bone marrow) from the subject is increased by about 17% to about 52% (e.g., about 17% to about 34%, about 26% to about 39%, or about 34% to about 52%), as compared to a reference level. In some embodiments, a level of CD4+PD1 + TEMRA cells in a sample (e.g., bone marrow) from the subject is increased by about 10% to about 29% (e.g., about 10% to about 19%, about 15% to about 22%, or about 19% to about 29%), as compared to a reference level. In some embodiments, a level of CD4+DR+KI67+ TN cells in a sample (e.g., bone marrow) from the subject is increased by about 41 % to about 124% (e.g., about 41 % to about 83%, about 62% to about 93%, or about 83% to about 124%), as compared to a reference level. In some embodiments, a level of CD4+DR+PD1 + TN cells in a sample (e.g., bone marrow) from the subject is increased by about 38% to about 1 13% (e.g., about 38% to about 75%, about 56% to about 85%, or about 75% to about 1 13%), as compared to a reference level. In some embodiments, a level of CD4+KI67+ TN cells in a sample (e.g., bone marrow) from the subject is increased by about 37% to about 1 10% (e.g., about 37% to about 73%, about 55% to about 82%, or about 73% to about 1 10%), as compared to a reference level. In some embodiments, a level of CD4+PD1 + TN cells in a sample (e.g., bone marrow) from the subject is increased by about 22% to about 67% (e.g., about 22% to about 45%, about 34% to about 50%, or about 45% to about 67%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +0X40+ TN cells in a sample (e.g., bone marrow) from the subject is increased by about 36% to about 107% (e.g., about 36% to about 71 %, about 53% to about 80%, or about 71 % to about 107%), as compared to a reference level. In some embodiments, a level of CD8+CD25-CD69+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 10% to about 29% (e.g., about 10% to about 19%, about 14% to about 21 %, or about 19% to about 29%), as compared to a reference level. In some embodiments, a level of CD8+DR+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 6% to about 17% (e.g., about 6% to about 1 1 %, about 9% to about 13%, or about 1 1 % to about 17%), as compared to a reference level. In some embodiments, a level of CD8+DR+GzB+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 9% to about 26% (e.g., about 9% to about 17%, about 13% to about 19%, or about 17% to about 26%), as compared to a reference level. In some embodiments, a level of CD8+DR+KI67+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 24% to about 72% (e.g., about 24% to about 48%, about 36% to about 54%, or about 48% to about 72%), as compared to a reference level. In some embodiments, a level of CD8+DR+PD1 + T cells in a sample (e.g., bone marrow) from the subject is increased by about 1 1 % to about 34% (e.g., about 1 1 % to about 22%, about 17% to about 25%, or about 22% to about 34%), as compared to a reference level. In some embodiments, a level of CD8+GzB+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 6% to about 19% (e.g., about 6% to about 12%, about 9% to about 14%, or about 12% to about 19%), as compared to a reference level. In some embodiments, a level of CD8+PD1 + T cells in a sample (e.g., bone marrow) from the subject is increased by about 6% to about 19% (e.g., about 6% to about 13%, about 9% to about 14%, or about 13% to about 19%), as compared to a reference level. In some embodiments, a level of CD8+PD1 +GzB+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 9% to about 27% (e.g., about 9% to about 18%, about 13% to about 20%, or about 18% to about 27%), as compared to a reference level. In some embodiments, a level of CD8+PD1 +OX40- T cells in a sample (e.g., bone marrow) from the subject is increased by about 8% to about 23% (e.g., about 8% to about 15%, about 11% to about 17%, or about 15% to about 23%), as compared to a reference level. In some embodiments, a level of CD8+DR+GzB+ TCM cells in a sample (e.g., bone marrow) from the subject is increased by about 21% to about 62% (e.g., about 21% to about 42%, about 31% to about 47%, or about 42% to about 62%), as compared to a reference level. In some embodiments, a level of CD8+DR+KI67+ TCM cells in a sample (e.g., bone marrow) from the subject is increased by about 26% to about 78% (e.g., about 26% to about 52%, about 39% to about 59%, or about 52% to about 78%), as compared to a reference level. In some embodiments, a level of CD8+DR+PD1 + TCM cells in a sample (e.g., bone marrow) from the subject is increased by about 19% to about 56% (e.g., about 19% to about 37%, about 28% to about 42%, or about 37% to about 56%), as compared to a reference level. In some embodiments, a level of CD8+GzB+ TCM cells in a sample (e.g., bone marrow) from the subject is increased by about 18% to about 54% (e.g., about 18% to about 36%, about 27% to about 41 %, or about 36% to about 54%), as compared to a reference level. In some embodiments, a level of CD8+KI67+ TCM cells in a sample (e.g., bone marrow) from the subject is increased by about 21 % to about 64% (e.g., about 21% to about 42%, about 32% to about 48%, or about 42% to about 64%), as compared to a reference level. In some embodiments, a level of CD8+PD1 + TCM cells in a sample (e.g., bone marrow) from the subject is increased by about 10% to about 31% (e.g., about 10% to about 21 %, about 15% to about 23%, or about 21% to about 31%), as compared to a reference level. In some embodiments, a level of CD8+DR+ TEM cells in a sample (e.g., bone marrow) from the subject is increased by about 7% to about 21% (e.g., about 7% to about 14%, about 11% to about 16%, or about 14% to about 21%), as compared to a reference level. In some embodiments, a level of CD8+DR+GzB+ TEM cells in a sample (e.g., bone marrow) from the subject is increased by about 9% to about 28% (e.g., about 9% to about 19%, about 14% to about 21 %, or about 19% to about 28%), as compared to a reference level. In some embodiments, a level of CD8+DR+KI67+ TEM cells in a sample (e.g., bone marrow) from the subject is increased by about 19% to about 56% (e.g., about 19% to about 37%, about 28% to about 42%, or about 37% to about 56%), as compared to a reference level. In some embodiments, a level of CD8+DR+PD1 + TEM cells in a sample (e.g., bone marrow) from the subject is increased by about 11% to about 33% (e.g., about 11% to about 22%, about 17% to about 25%, or about 22% to about 33%), as compared to a reference level. In some embodiments, a level of CD8+GzB+ TEM cells in a sample (e.g., bone marrow) from the subject is increased by about 7% to about 20% (e.g., about 7% to about 13%, about 10% to about 15%, or about 13% to about 20%), as compared to a reference level. In some embodiments, a level of CD8+PD1 + TEM cells in a sample (e.g., bone marrow) from the subject is increased by about 6% to about 19% (e.g., about 6% to about 13%, about 9% to about 14%, or about 13% to about 19%), as compared to a reference level. In some embodiments, a level of CD8+DR+PD1 + TEMRA cells in a sample (e.g., bone marrow) from the subject is increased by about 8% to about 23% (e.g., about 8% to about 15%, about 11 % to about 17%, or about 15% to about 23%), as compared to a reference level. In some embodiments, a level of CD8+DR+ TN cells in a sample (e.g., bone marrow) from the subject is increased by about 9% to about 27% (e.g., about 9% to about 18%, about 14% to about 20%, or about 18% to about 27%), as compared to a reference level. In some embodiments, a level of CD8+DR+GzB+ TN cells in a sample (e.g., bone marrow) from the subject is increased by about 22% to about 65% (e.g., about 22% to about 43%, about 32% to about 49%, or about 43% to about 65%), as compared to a reference level. In some embodiments, a level of CD8+DR+KI67+ TN cells in a sample (e.g., bone marrow) from the subject is increased by about 30% to about 91% (e.g., about 30% to about 61%, about 46% to about 69%, or about 61% to about 91%), as compared to a reference level. In some embodiments, a level of CD8+DR+PD1 + TN cells in a sample (e.g., bone marrow) from the subject is increased by about 20% to about 59% (e.g., about 20% to about 39%, about 30% to about 44%, or about 39% to about 59%), as compared to a reference level. In some embodiments, a level of CD8+KI67+ TN cells in a sample (e.g., bone marrow) from the subject is increased by about 28% to about 85% (e.g., about 28% to about 57%, about 43% to about 64%, or about 57% to about 85%), as compared to a reference level. In some embodiments, a level of CD8+PD1 + TN cells in a sample (e.g., bone marrow) from the subject is increased by about 10% to about 29% (e.g., about 10% to about 20%, about 15% to about 22%, or about 20% to about 29%), as compared to a reference level. In some embodiments, a level of CD3-DR+ cells in a sample (e.g., bone marrow) from the subject is increased by about 10% to about 30% (e.g., about 10% to about 20%, about 15% to about 22%, or about 20% to about 30%), as compared to a reference level. In some embodiments, a level of 0X40+ Treg cells in a sample (e.g., bone marrow) from the subject is increased by about 13% to about 38% (e.g., about 13% to about 26%, about 19% to about 29%, or about 26% to about 38%), as compared to a reference level. In some embodiments, a level of PD1 +OX40+ Treg cells in a sample (e.g., bone marrow) from the subject is increased by about 16% to about 48% (e.g., about 16% to about 32%, about 24% to about 36%, or about 32% to about 48%), as compared to a reference level. In some embodiments, a level of true NK cells in a sample (e.g., bone marrow) from the subject is increased by about 7% to about 22% (e.g., about 7% to about 15%, about 11 % to about 17%, or about 15% to about 22%), as compared to a reference level.

Table 6. Cell Types in Bone Marrow that are Associated with Increased Resistance to Cevostamab

CD = cluster of differentiation; DR = human leukocyte antigen - DR isotype; Ki67 = antigen Kiel 67; PD1 = programmed cell death protein 1 ; GzB = Granzyme B; TIGIT = T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains; TIM3 = T cell immunoglobulin and mucin-domain containing-3; TN cells = naive T cells; TCM cells = central memory T cells; TEM cells = effector memory T cells; TEMRA cells= terminally differentiated effector memory T cells; Treg cells = regulatory T cells; NK cells = natural killer cells

Conversely, MM subjects having a decreased level (e.g., presence or percentage) of one or more (e.g., one, two, three, four, five, six, seven, eight, nine, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, or all 69) cell types set forth in Table 6 in a bone marrow sample (e.g., a baseline bone marrow sample), as compared to a reference level, are generally more sensitive to treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab). For example, in some embodiments, a level of CD4+CD25- CD69+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 11% to about 32% (e.g., about 11 % to about 21 %, about 16% to about 24%, or about 21 % to about 32%), as compared to a reference level. In some embodiments, a level of CD4+DR+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 6% to about 17% (e.g., about 6% to about 12%, about 9% to about 13%, or about 12% to about 17%), as compared to a reference level. In some embodiments, a level of CD4+DR+GzB+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 7% to about 21% (e.g., about 7% to about 14%, about 10% to about 15%, or about 14% to about 21%), as compared to a reference level. In some embodiments, a level of CD4+DR+KI67+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 11% to about 33% (e.g., about 11% to about 22%, about 17% to about 25%, or about 22% to about 33%), as compared to a reference level. In some embodiments, a level of CD4+DR+PD1 + T cells in a sample (e.g., bone marrow) from the subject is decreased by about 10% to about 31 % (e.g., about 10% to about 20%, about 15% to about 23%, or about 20% to about 31 %), as compared to a reference level. In some embodiments, a level of CD4+KI67+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 9% to about 27% (e.g., about 9% to about 18%, about 14% to about 20%, or about 18% to about 27%), as compared to a reference level. In some embodiments, a level of CD4+PD1 + T cells in a sample (e.g., bone marrow) from the subject is decreased by about 5% to about 16% (e.g., about 5% to about 1 1 %, about 8% to about 12%, or about 1 1 % to about 16%), as compared to a reference level. In some embodiments, a level of CD4+PD1 + T cells in a sample (e.g., bone marrow) from the subject is decreased by about 6% to about 18% (e.g., about 6% to about 12%, about 9% to about 13%, or about 12% to about 18%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +GzB+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 7% to about 22% (e.g., about 7% to about 15%, about 1 1 % to about 16%, or about 15% to about 22%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +KI67+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 12% to about 36% (e.g., about 12% to about 24%, about 18% to about 27%, or about 24% to about 36%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +OX40- T cells in a sample (e.g., bone marrow) from the subject is decreased by about 5% to about 14% (e.g., about 5% to about 10%, about 7% to about 1 1 %, or about 10% to about 14%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +OX40+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 5% to about 14% (e.g., about 5% to about 9%, about 7% to about 10%, or about 9% to about 14%), as compared to a reference level. In some embodiments, a level of CD4+PD1 -TIGIT+TIM3- T cells in a sample (e.g., bone marrow) from the subject is decreased by about 3% to about 10% (e.g., about 3% to about 7%, about 5% to about 8%, or about 7% to about 10%), as compared to a reference level. In some embodiments, a level of CD4+TIGIT+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 4% to about 12% (e.g., about 4% to about 8%, about 6% to about 9%, or about 8% to about 12%), as compared to a reference level. In some embodiments, a level of CD4+DR+ TCM cells in a sample (e.g., bone marrow) from the subject is decreased by about 9% to about 28% (e.g., about 9% to about 19%, about 14% to about 21 %, or about 19% to about 28%), as compared to a reference level. In some embodiments, a level of CD4+DR+KI67+ TCM cells in a sample (e.g., bone marrow) from the subject is decreased by about 12% to about 36% (e.g., about 12% to about 24%, about 18% to about 27%, or about 24% to about 36%), as compared to a reference level. In some embodiments, a level of CD4+DR+PD1 + TCM cells in a sample (e.g., bone marrow) from the subject is decreased by about 14% to about 42% (e.g., about 14% to about 28%, about 21 % to about 31 %, or about 28% to about 42%), as compared to a reference level. In some embodiments, a level of CD4+KI67+ TCM cells in a sample (e.g., bone marrow) from the subject is decreased by about 9% to about 27% (e.g., about 9% to about 18%, about 14% to about 20%, or about 18% to about 27%), as compared to a reference level. In some embodiments, a level of CD4+PD1 + TCM cells in a sample (e.g., bone marrow) from the subject is decreased by about 7% to about 21 % (e.g., about 7% to about 14%, about 10% to about 15%, or about 14% to about 21 %), as compared to a reference level. In some embodiments, a level of CD4+PD1 +OX40+ TCM cells in a sample (e.g., bone marrow) from the subject is decreased by about 6% to about 17% (e.g., about 6% to about 1 1 %, about 8% to about 12%, or about 1 1 % to about 17%), as compared to a reference level. In some embodiments, a level of CD4+DR+ TEM cells in a sample (e.g., bone marrow) from the subject is decreased by about 4% to about 12% (e.g., about 4% to about 8%, about 6% to about 9%, or about 8% to about 12%), as compared to a reference level. In some embodiments, a level of CD4+DR+KI67+ TEM cells in a sample (e.g., bone marrow) from the subject is decreased by about 8% to about 24% (e.g., about 8% to about 16%, about 12% to about 18%, or about 16% to about 24%), as compared to a reference level. In some embodiments, a level of CD4+DR+PD1 + TEM cells in a sample (e.g., bone marrow) from the subject is decreased by about 7% to about 21 % (e.g., about 7% to about 14%, about 10% to about 16%, or about 14% to about 21 %), as compared to a reference level. In some embodiments, a level of CD4+KI67+ TEM cells in a sample (e.g., bone marrow) from the subject is decreased by about 7% to about 21 % (e.g., about 7% to about 14%, about 10% to about 15%, or about 14% to about 21 %), as compared to a reference level. In some embodiments, a level of CD4+PD1 + TEM cells in a sample (e.g., bone marrow) from the subject is decreased by about 4% to about 1 1 % (e.g., about 4% to about 7%, about 5% to about 8%, or about 7% to about 1 1 %), as compared to a reference level. In some embodiments, a level of CD4+ TEM cells in a sample (e.g., bone marrow) from the subject is decreased by about 2% to about 7% (e.g., about 2% to about 5%, about 4% to about 6%, or about 5% to about 7%), as compared to a reference level. In some embodiments, a level of CD4+ TEM cells in a sample (e.g., bone marrow) from the subject is decreased by about 2% to about 7% (e.g., about 2% to about 5%, about 4% to about 5%, or about 5% to about 7%), as compared to a reference level. In some embodiments, a level of CD4+DR+ TEMRA cells in a sample (e.g., bone marrow) from the subject is decreased by about 4% to about 12% (e.g., about 4% to about 8%, about 6% to about 9%, or about 8% to about 12%), as compared to a reference level. In some embodiments, a level of CD4+DR+GzB+ TEMRA cells in a sample (e.g., bone marrow) from the subject is decreased by about 4% to about 13% (e.g., about 4% to about 9%, about 6% to about 10%, or about 9% to about 13%), as compared to a reference level. In some embodiments, a level of CD4+DR+KI67+ TEMRA cells in a sample (e.g., bone marrow) from the subject is decreased by about 7% to about 22% (e.g., about 7% to about 15%, about 1 1 % to about 17%, or about 15% to about 22%), as compared to a reference level. In some embodiments, a level of CD4+DR+PD1 + TEMRA cells in a sample (e.g., bone marrow) from the subject is decreased by about 7% to about 21 % (e.g., about 7% to about 14%, about 10% to about 15%, or about 14% to about 21 %), as compared to a reference level. In some embodiments, a level of CD4+KI67+ TEMRA cells in a sample (e.g., bone marrow) from the subject is decreased by about 7% to about 21 % (e.g., about 7% to about 14%, about 10% to about 15%, or about 14% to about 21 %), as compared to a reference level. In some embodiments, a level of CD4+PD1 + TEMRA cells in a sample (e.g., bone marrow) from the subject is decreased by about 4% to about 12% (e.g., about 4% to about 8%, about 6% to about 9%, or about 8% to about 12%), as compared to a reference level. In some embodiments, a level of CD4+DR+KI67+ TN cells in a sample (e.g., bone marrow) from the subject is decreased by about 17% to about 50% (e.g., about 17% to about 33%, about 25% to about 37%, or about 33% to about 50%), as compared to a reference level. In some embodiments, a level of CD4+DR+PD1 + TN cells in a sample (e.g., bone marrow) from the subject is decreased by about 15% to about 45% (e.g., about 15% to about 30%, about 22% to about 34%, or about 30% to about 45%), as compared to a reference level. In some embodiments, a level of CD4+KI67+ TN cells in a sample (e.g., bone marrow) from the subject is decreased by about 15% to about 44% (e.g., about 15% to about 29%, about 22% to about 33%, or about 29% to about 44%), as compared to a reference level. In some embodiments, a level of CD4+PD1 + TN cells in a sample (e.g., bone marrow) from the subject is decreased by about 9% to about 27% (e.g., about 9% to about 18%, about 13% to about 20%, or about 18% to about 27%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +0X40+ TN cells in a sample (e.g., bone marrow) from the subject is decreased by about 14% to about 42% (e.g., about 14% to about 28%, about 21% to about 32%, or about 28% to about 42%), as compared to a reference level. In some embodiments, a level of CD8+CD25-CD69+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 4% to about 11% (e.g., about 4% to about 8%, about 6% to about 9%, or about 8% to about 11%), as compared to a reference level. In some embodiments, a level of CD8+DR+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 2% to about 7% (e.g., about 2% to about 5%, about 3% to about 5%, or about 5% to about 7%), as compared to a reference level. In some embodiments, a level of CD8+DR+GzB+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 3% to about 10% (e.g., about 3% to about 7%, about 5% to about 8%, or about 7% to about 10%), as compared to a reference level. In some embodiments, a level of CD8+DR+KI67+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 10% to about 29% (e.g., about 10% to about 19%, about 14% to about 22%, or about 19% to about 29%), as compared to a reference level. In some embodiments, a level of CD8+DR+PD1 + T cells in a sample (e.g., bone marrow) from the subject is decreased by about 4% to about 13% (e.g., about 4% to about 9%, about 7% to about 10%, or about 9% to about 13%), as compared to a reference level. In some embodiments, a level of CD8+GzB+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 2% to about 7% (e.g., about 2% to about 5%, about 4% to about 6%, or about 5% to about 7%), as compared to a reference level. In some embodiments, a level of CD8+PD1 + T cells in a sample (e.g., bone marrow) from the subject is decreased by about 3% to about 8% (e.g., about 3% to about 5%, about 4% to about 6%, or about 5% to about 8%), as compared to a reference level. In some embodiments, a level of CD8+PD1 +GzB+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 4% to about 11% (e.g., about 4% to about 7%, about 5% to about 8%, or about 7% to about 11%), as compared to a reference level. In some embodiments, a level of CD8+PD1 +OX40- T cells in a sample (e.g., bone marrow) from the subject is decreased by about 3% to about 9% (e.g., about 3% to about 6%, about 5% to about 7%, or about 6% to about 9%), as compared to a reference level. In some embodiments, a level of CD8+DR+GzB+ TCM cells in a sample (e.g., bone marrow) from the subject is decreased by about 8% to about 25% (e.g., about 8% to about 17%, about 12% to about 19%, or about 17% to about 25%), as compared to a reference level. In some embodiments, a level of CD8+DR+KI67+ TCM cells in a sample (e.g., bone marrow) from the subject is decreased by about 10% to about 31 % (e.g., about 10% to about 21 %, about 16% to about 23%, or about 21 % to about 31 %), as compared to a reference level. In some embodiments, a level of CD8+DR+PD1 + TCM cells in a sample (e.g., bone marrow) from the subject is decreased by about 7% to about 22% (e.g., about 7% to about 15%, about 1 1 % to about 17%, or about 15% to about 22%), as compared to a reference level. In some embodiments, a level of CD8+GzB+ TCM cells in a sample (e.g., bone marrow) from the subject is decreased by about 7% to about 22% (e.g., about 7% to about 14%, about 1 1 % to about 16%, or about 14% to about 22%), as compared to a reference level. In some embodiments, a level of CD8+KI67+ TCM cells in a sample (e.g., bone marrow) from the subject is decreased by about 8% to about 25% (e.g., about 8% to about 17%, about 13% to about 19%, or about 17% to about 25%), as compared to a reference level. In some embodiments, a level of CD8+PD1 + TCM cells in a sample (e.g., bone marrow) from the subject is decreased by about 4% to about 12% (e.g., about 4% to about 8%, about 6% to about 9%, or about 8% to about 12%), as compared to a reference level. In some embodiments, a level of CD8+DR+ TEM cells in a sample (e.g., bone marrow) from the subject is decreased by about 3% to about 9% (e.g., about 3% to about 6%, about 4% to about 6%, or about 6% to about 9%), as compared to a reference level. In some embodiments, a level of CD8+DR+GzB+ TEM cells in a sample (e.g., bone marrow) from the subject is decreased by about 4% to about 1 1 % (e.g., about 4% to about 8%, about 6% to about 8%, or about 8% to about 1 1 %), as compared to a reference level. In some embodiments, a level of CD8+DR+KI67+ TEM cells in a sample (e.g., bone marrow) from the subject is decreased by about 7% to about 22% (e.g., about 7% to about 15%, about 1 1 % to about 17%, or about 15% to about 22%), as compared to a reference level. In some embodiments, a level of CD8+DR+PD1 + TEM cells in a sample (e.g., bone marrow) from the subject is decreased by about 4% to about 13% (e.g., about 4% to about 9%, about 7% to about 10%, or about 9% to about 13%), as compared to a reference level. In some embodiments, a level of CD8+GzB+ TEM cells in a sample (e.g., bone marrow) from the subject is decreased by about 3% to about 8% (e.g., about 3% to about 5%, about 4% to about 6%, or about 5% to about 8%), as compared to a reference level. In some embodiments, a level of CD8+PD1 + TEM cells in a sample (e.g., bone marrow) from the subject is decreased by about 2% to about 7% (e.g., about 2% to about 5%, about 4% to about 6%, or about 5% to about 7%), as compared to a reference level. In some embodiments, a level of CD8+DR+PD1 + TEMRA cells in a sample (e.g., bone marrow) from the subject is decreased by about 3% to about 9% (e.g., about 3% to about 6%, about 5% to about 7%, or about 6% to about 9%), as compared to a reference level. In some embodiments, a level of CD8+DR+ TN cells in a sample (e.g., bone marrow) from the subject is decreased by about 4% to about 1 1 % (e.g., about 4% to about 7%, about 5% to about 8%, or about 7% to about 1 1 %), as compared to a reference level. In some embodiments, a level of CD8+DR+GzB+ TN cells in a sample (e.g., bone marrow) from the subject is decreased by about 9% to about 26% (e.g., about 9% to about 17%, about 13% to about 19%, or about 17% to about 26%), as compared to a reference level. In some embodiments, a level of CD8+DR+KI67+ TN cells in a sample (e.g., bone marrow) from the subject is decreased by about 12% to about 36% (e.g., about 12% to about 24%, about 18% to about 27%, or about 24% to about 36%), as compared to a reference level. In some embodiments, a level of CD8+DR+PD1 + TN cells in a sample (e.g., bone marrow) from the subject is decreased by about 8% to about 24% (e.g., about 8% to about 16%, about 12% to about 18%, or about 16% to about 24%), as compared to a reference level. In some embodiments, a level of CD8+KI67+ TN cells in a sample (e.g., bone marrow) from the subject is decreased by about 1 1 % to about 34% (e.g., about 1 1 % to about 23%, about 17% to about 25%, or about 23% to about 34%), as compared to a reference level. In some embodiments, a level of CD8+PD1 + TN cells in a sample (e.g., bone marrow) from the subject is decreased by about 4% to about 12% (e.g., about 4% to about 8%, about 6% to about 9%, or about 8% to about 12%), as compared to a reference level. In some embodiments, a level of CD3-DR+ cells in a sample (e.g., bone marrow) from the subject is decreased by about 4% to about 12% (e.g., about 4% to about 8%, about 6% to about 9%, or about 8% to about 12%), as compared to a reference level. In some embodiments, a level of 0X40+ Treg cells in a sample (e.g., bone marrow) from the subject is decreased by about 5% to about 15% (e.g., about 5% to about 10%, about 8% to about 1 1 %, or about 10% to about 15%), as compared to a reference level. In some embodiments, a level of PD1 +OX40+ Treg cells in a sample (e.g., bone marrow) from the subject is decreased by about 6% to about 19% (e.g., about 6% to about 13%, about 9% to about 14%, or about 13% to about 19%), as compared to a reference level. In some embodiments, a level of true NK cells in a sample (e.g., bone marrow) from the subject is decreased by about 3% to about 9% (e.g., about 3% to about 6%, about 4% to about 7%, or about 6% to about 9%), as compared to a reference level.

Cell types in bone marrow that are associated with increased sensitivity to cevostamab In some aspects of the invention, the methods described herein require determining a level of one or more cell types set forth in Table 7 in the bone marrow of the subject. In some aspects of the invention, the methods described herein require that a level of one or more cell types set forth in Table 7 has been previously determined in the bone marrow of the subject.

In general, MM subjects having an increased level (e.g., presence or percentage) of one or more (e.g., one, two, three, four, five, six, seven, or all eight) cell types set forth in Table 7 in a bone marrow sample (e.g., a baseline bone marrow sample), as compared to a reference level, are more sensitive to treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab). For example, in some embodiments, a level of CD4+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 4% to about 12% (e.g., about 4% to about 8%, about 6% to about 9%, or about 8% to about 12%), as compared to a reference level. In some embodiments, a level of CD4+CD25+CD69- T cells in a sample (e.g., bone marrow) from the subject is increased by about 3% to about 10% (e.g., about 3% to about 7%, about 5% to about 7%, or about 7% to about 10%), as compared to a reference level. In some embodiments, a level of CD4+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 3% to about 10% (e.g., about 3% to about 7%, about 5% to about 8%, or about 7% to about 10%), as compared to a reference level. In some embodiments, a level of CD4+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 5% to about 14% (e.g., about 5% to about 9%, about 7% to about 11%, or about 9% to about 14%), as compared to a reference level. In some embodiments, a level of CD4+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 4% to about 12% (e.g., about 4% to about 8%, about 6% to about 9%, or about 8% to about 12%), as compared to a reference level. In some embodiments, a level of CD4+ TCM cells in a sample (e.g., bone marrow) from the subject is increased by about 4% to about 11% (e.g., about 4% to about 7%, about 5% to about 8%, or about 7% to about 11%), as compared to a reference level. In some embodiments, a level of CD4+ TCM cells in a sample (e.g., bone marrow) from the subject is increased by about 4% to about 11% (e.g., about 4% to about 7%, about 5% to about 8%, or about 7% to about 11%), as compared to a reference level. In some embodiments, a level of CD8+CD25+CD69- T cells in a sample (e.g., bone marrow) from the subject is increased by about 11% to about 33% (e.g., about 11% to about 22%, about 17% to about 25%, or about 22% to about 33%), as compared to a reference level. In some embodiments, a level of CD8+NK T cells in a sample (e.g., bone marrow) from the subject is increased by about 3% to about 9% (e.g., about 3% to about 6%, about 5% to about 7%, or about 6% to about 9%), as compared to a reference level. In some embodiments, a level of CD8+ TCM cells in a sample (e.g., bone marrow) from the subject is increased by about 8% to about 25% (e.g., about 8% to about 16%, about 12% to about 18%, or about 16% to about 25%), as compared to a reference level. In some embodiments, a level of CD8+ TCM cells in a sample (e.g., bone marrow) from the subject is increased by about 9% to about 26% (e.g., about 9% to about 17%, about 13% to about 19%, or about 17% to about 26%), as compared to a reference level. In some embodiments, a level of CD8+ TN cells in a sample (e.g., bone marrow) from the subject is increased by about 6% to about 19% (e.g., about 6% to about 12%, about 9% to about 14%, or about 12% to about 19%), as compared to a reference level. In some embodiments, a level of CD8+ TN cells in a sample (e.g., bone marrow) from the subject is increased by about 8% to about 23% (e.g., about 8% to about 15%, about 11 % to about 17%, or about 15% to about 23%), as compared to a reference level. In some embodiments, a level of CD25+CD69- NK cells in a sample (e.g., bone marrow) from the subject is increased by about 5% to about 15% (e.g., about 5% to about 10%, about 8% to about 11%, or about 10% to about 15%), as compared to a reference level.

Table 7. Cell Types in Bone Marrow that are Associated with Increased Sensitivity to Cevostamab

CD = cluster of differentiation; NK T cells = natural killer T cells; TN cells = naive T cells; TCM cells = central memory T cells; NK cells = natural killer cells Conversely, MM subjects having a decreased level (e.g., presence or percentage) of one or more (e.g., one, two, three, four, five, six, seven, or all eight) cell types set forth in Table 7 in a bone marrow sample (e.g., a baseline bone marrow sample), as compared to a reference level, are more resistant to treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab). For example, in some embodiments, a level of CD4+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 10% to about 29% (e.g., about 10% to about 19%, about 15% to about 22%, or about 19% to about 29%), as compared to a reference level. In some embodiments, a level of CD4+CD25+CD69- T cells in a sample (e.g., bone marrow) from the subject is decreased by about 8% to about 25% (e.g., about 8% to about 16%, about 12% to about 18%, or about 16% to about 25%), as compared to a reference level. In some embodiments, a level of CD4+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 9% to about 26% (e.g., about 9% to about 17%, about 13% to about 19%, or about 17% to about 26%), as compared to a reference level. In some embodiments, a level of CD4+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 12% to about 36% (e.g., about 12% to about 24%, about 18% to about 27%, or about 24% to about 36%), as compared to a reference level. In some embodiments, a level of CD4+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 10% to about 31% (e.g., about 10% to about 21 %, about 16% to about 23%, or about 21 % to about 31 %), as compared to a reference level. In some embodiments, a level of CD4+ TCM cells in a sample (e.g., bone marrow) from the subject is decreased by about 9% to about 27% (e.g., about 9% to about 18%, about 14% to about 20%, or about 18% to about 27%), as compared to a reference level. In some embodiments, a level of CD4+ TCM cells in a sample (e.g., bone marrow) from the subject is decreased by about 9% to about 27% (e.g., about 9% to about 18%, about 14% to about 20%, or about 18% to about 27%), as compared to a reference level. In some embodiments, a level of CD8+CD25+CD69- T cells in a sample (e.g., bone marrow) from the subject is decreased by about 28% to about 83% (e.g., about 28% to about 55%, about 41% to about 62%, or about 55% to about 83%), as compared to a reference level. In some embodiments, a level of CD8+NK T cells in a sample (e.g., bone marrow) from the subject is decreased by about 8% to about 23% (e.g., about 8% to about 16%, about 12% to about 17%, or about 16% to about 23%), as compared to a reference level. In some embodiments, a level of CD8+ TCM cells in a sample (e.g., bone marrow) from the subject is decreased by about 20% to about 61% (e.g., about 20% to about 41%, about 31 % to about 46%, or about 41% to about 61%), as compared to a reference level. In some embodiments, a level of CD8+ TCM cells in a sample (e.g., bone marrow) from the subject is decreased by about 21% to about 64% (e.g., about 21% to about 43%, about 32% to about 48%, or about 43% to about 64%), as compared to a reference level. In some embodiments, a level of CD8+ TN cells in a sample (e.g., bone marrow) from the subject is decreased by about 16% to about 47% (e.g., about 16% to about 31 %, about 23% to about 35%, or about 31 % to about 47%), as compared to a reference level. In some embodiments, a level of CD8+ TN cells in a sample (e.g., bone marrow) from the subject is decreased by about 19% to about 57% (e.g., about 19% to about 38%, about 29% to about 43%, or about 38% to about 57%), as compared to a reference level. In some embodiments, a level of CD25+CD69- NK cells in a sample (e.g., bone marrow) from the subject is decreased by about 13% to about 38% (e.g., about 13% to about 25%, about 19% to about 29%, or about 25% to about 38%), as compared to a reference level.

Cell types in blood that are associated with increased resistance to cevostamab

In some aspects of the invention, the methods described herein require determining a level of one or more cell types set forth in Table 8 in the blood (e.g., whole blood, serum, or plasma) of the subject. In some aspects of the invention, the methods described herein require that a level of one or more cell types set forth in Table 8 has been previously determined in the blood of the subject.

In general, MM subjects having an increased level (e.g., presence or percentage) of one or more (e.g., one, two, three, four, five, six, seven, eight, nine, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, or all 80) cell types set forth in Table 8 in a blood sample (e.g., a baseline blood sample), as compared to a reference level, are more resistant to treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab). For example, in some embodiments, a level of CD8+DR+ TCM cells in a sample (e.g., bone marrow) from the subject is increased by about 14% to about 43% (e.g., about 14% to about 29%, about 22% to about 32%, or about 29% to about 43%), as compared to a reference level. In some embodiments, a level of CD4+DR+ T cells in a sample (e.g., blood) from the subject is increased by about 19% to about 57% (e.g., about 19% to about 38%, about 28% to about 42%, or about 38% to about 57%), as compared to a reference level. In some embodiments, a level of CD4+DR+GzB+ T cells in a sample (e.g., blood) from the subject is increased by about 17% to about 51 % (e.g., about 17% to about 34%, about 26% to about 38%, or about 34% to about 51%), as compared to a reference level. In some embodiments, a level of CD4+DR+KI67+ T cells in a sample (e.g., blood) from the subject is increased by about 24% to about 73% (e.g., about 24% to about 49%, about 37% to about 55%, or about 49% to about 73%), as compared to a reference level. In some embodiments, a level of CD4+DR+PD1 + T cells in a sample (e.g., blood) from the subject is increased by about 26% to about 79% (e.g., about 26% to about 53%, about 39% to about 59%, or about 53% to about 79%), as compared to a reference level. In some embodiments, a level of CD4+KI67+ T cells in a sample (e.g., blood) from the subject is increased by about 22% to about 65% (e.g., about 22% to about 43%, about 32% to about 48%, or about 43% to about 65%), as compared to a reference level. In some embodiments, a level of CD4+PD1 + T cells in a sample (e.g., blood) from the subject is increased by about 13% to about 38% (e.g., about 13% to about 26%, about 19% to about 29%, or about 26% to about 38%), as compared to a reference level. In some embodiments, a level of CD4+PD1 + T cells in a sample (e.g., blood) from the subject is increased by about 14% to about 41 % (e.g., about 14% to about 27%, about 21 % to about 31 %, or about 27% to about 41%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +KI67+ T cells in a sample (e.g., blood) from the subject is increased by about 26% to about 77% (e.g., about 26% to about 52%, about 39% to about 58%, or about 52% to about 77%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +OX40- T cells in a sample (e.g., blood) from the subject is increased by about 5% to about 15% (e.g., about 5% to about 10%, about 7% to about 11 %, or about 10% to about 15%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +0X40+ T cells in a sample (e.g., blood) from the subject is increased by about 11% to about 34% (e.g., about 11% to about 23%, about 17% to about 26%, or about 23% to about 34%), as compared to a reference level. In some embodiments, a level of CD4+PD1 -TIGIT+TIM3- T cells in a sample (e.g., blood) from the subject is increased by about 12% to about 35% (e.g., about 12% to about 23%, about 17% to about 26%, or about 23% to about 35%), as compared to a reference level. In some embodiments, a level of CD4+PDL1 + T cells in a sample (e.g., blood) from the subject is increased by about 15% to about 45% (e.g., about 15% to about 30%, about 23% to about 34%, or about 30% to about 45%), as compared to a reference level. In some embodiments, a level of CD4+TIGIT+ T cells in a sample (e.g., blood) from the subject is increased by about 11 % to about 34% (e.g., about 11 % to about 23%, about 17% to about 26%, or about 23% to about 34%), as compared to a reference level. In some embodiments, a level of CD4+DR+ TCM cells in a sample (e.g., blood) from the subject is increased by about 26% to about 77% (e.g., about 26% to about 52%, about 39% to about 58%, or about 52% to about 77%), as compared to a reference level. In some embodiments, a level of CD4+DR+KI67+ TCM cells in a sample (e.g., blood) from the subject is increased by about 25% to about 74% (e.g., about 25% to about 49%, about 37% to about 55%, or about 49% to about 74%), as compared to a reference level. In some embodiments, a level of CD4+DR+PD1 + TCM cells in a sample (e.g., blood) from the subject is increased by about 34% to about 102% (e.g., about 34% to about 68%, about 51 % to about 76%, or about 68% to about 102%), as compared to a reference level. In some embodiments, a level of CD4+KI67+ TCM cells in a sample (e.g., blood) from the subject is increased by about 19% to about 57% (e.g., about 19% to about 38%, about 28% to about 43%, or about 38% to about 57%), as compared to a reference level. In some embodiments, a level of CD4+PD1 + TCM cells in a sample (e.g., blood) from the subject is increased by about 15% to about 46% (e.g., about 15% to about 31 %, about 23% to about 35%, or about 31 % to about 46%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +OX40+ TCM cells in a sample (e.g., blood) from the subject is increased by about 12% to about 37% (e.g., about 12% to about 25%, about 18% to about 28%, or about 25% to about 37%), as compared to a reference level. In some embodiments, a level of CD4+DR+ TEM cells in a sample (e.g., blood) from the subject is increased by about 13% to about 38% (e.g., about 13% to about 26%, about 19% to about 29%, or about 26% to about 38%), as compared to a reference level. In some embodiments, a level of CD4+DR+KI67+ TEM cells in a sample (e.g., blood) from the subject is increased by about 19% to about 57% (e.g., about 19% to about 38%, about 28% to about 43%, or about 38% to about 57%), as compared to a reference level. In some embodiments, a level of CD4+DR+PD1 + TEM cells in a sample (e.g., blood) from the subject is increased by about 18% to about 53% (e.g., about 18% to about 35%, about 27% to about 40%, or about 35% to about 53%), as compared to a reference level. In some embodiments, a level of CD4+KI67+ TEM cells in a sample (e.g., blood) from the subject is increased by about 18% to about 53% (e.g., about 18% to about 35%, about 27% to about 40%, or about 35% to about 53%), as compared to a reference level. In some embodiments, a level of CD4+PD1 + TEM cells in a sample (e.g., blood) from the subject is increased by about 8% to about 24% (e.g., about 8% to about 16%, about 12% to about 18%, or about 16% to about 24%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +OX40+ TEM cells in a sample (e.g., blood) from the subject is increased by about 8% to about 23% (e.g., about 8% to about 15%, about 1 1 % to about 17%, or about 15% to about 23%), as compared to a reference level. In some embodiments, a level of CD4+DR+ TEMRA cells in a sample (e.g., blood) from the subject is increased by about 15% to about 46% (e.g., about 15% to about 31 %, about 23% to about 35%, or about 31 % to about 46%), as compared to a reference level. In some embodiments, a level of CD4+DR+GzB+ TEMRA cells in a sample (e.g., blood) from the subject is increased by about 14% to about 41 % (e.g., about 14% to about 27%, about 20% to about 31 %, or about 27% to about 41 %), as compared to a reference level. In some embodiments, a level of CD4+DR+KI67+ TEMRA cells in a sample (e.g., blood) from the subject is increased by about 23% to about 68% (e.g., about 23% to about 46%, about 34% to about 51 %, or about 46% to about 68%), as compared to a reference level. In some embodiments, a level of CD4+DR+PD1 + TEMRA cells in a sample (e.g., blood) from the subject is increased by about 21 % to about 63% (e.g., about 21 % to about 42%, about 31 % to about 47%, or about 42% to about 63%), as compared to a reference level. In some embodiments, a level of CD4+KI67+ TEMRA cells in a sample (e.g., blood) from the subject is increased by about 21 % to about 63% (e.g., about 21 % to about 42%, about 32% to about 47%, or about 42% to about 63%), as compared to a reference level. In some embodiments, a level of CD4+PD1 + TEMRA cells in a sample (e.g., blood) from the subject is increased by about 9% to about 28% (e.g., about 9% to about 19%, about 14% to about 21 %, or about 19% to about 28%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +0X40+ TEMRA cells in a sample (e.g., blood) from the subject is increased by about 10% to about 29% (e.g., about 10% to about 20%, about 15% to about 22%, or about 20% to about 29%), as compared to a reference level. In some embodiments, a level of CD4+DR+ TN cells in a sample (e.g., blood) from the subject is increased by about 19% to about 58% (e.g., about 19% to about 39%, about 29% to about 44%, or about 39% to about 58%), as compared to a reference level. In some embodiments, a level of CD4+DR+KI67+ TN cells in a sample (e.g., blood) from the subject is increased by about 38% to about 1 14% (e.g., about 38% to about 76%, about 57% to about 85%, or about 76% to about 1 14%), as compared to a reference level. In some embodiments, a level of CD4+DR+PD1 + TN cells in a sample (e.g., blood) from the subject is increased by about 53% to about 160% (e.g., about 53% to about 107%, about 80% to about 120%, or about 107% to about 160%), as compared to a reference level. In some embodiments, a level of CD4+KI67+ TN cells in a sample (e.g., blood) from the subject is increased by about 27% to about 81 % (e.g., about 27% to about 54%, about 41 % to about 61 %, or about 54% to about 81 %), as compared to a reference level. In some embodiments, a level of CD4+PD1 + TN cells in a sample (e.g., blood) from the subject is increased by about 19% to about 58% (e.g., about 19% to about 39%, about 29% to about 44%, or about 39% to about 58%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +0X40+ TN cells in a sample (e.g., blood) from the subject is increased by about 18% to about 54% (e.g., about 18% to about 36%, about 27% to about 41 %, or about 36% to about 54%), as compared to a reference level. In some embodiments, a level of CD8+DR+ T cells in a sample (e.g., blood) from the subject is increased by about 8% to about 25% (e.g., about 8% to about 17%, about 13% to about 19%, or about 17% to about 25%), as compared to a reference level. In some embodiments, a level of CD8+DR+GzB+ T cells in a sample (e.g., blood) from the subject is increased by about 9% to about 28% (e.g., about 9% to about 18%, about 14% to about 21 %, or about 18% to about 28%), as compared to a reference level. In some embodiments, a level of CD8+DR+KI67+ T cells in a sample (e.g., blood) from the subject is increased by about 25% to about 74% (e.g., about 25% to about 49%, about 37% to about 56%, or about 49% to about 74%), as compared to a reference level. In some embodiments, a level of CD8+DR+PD1 + T cells in a sample (e.g., blood) from the subject is increased by about 15% to about 44% (e.g., about 15% to about 29%, about 22% to about 33%, or about 29% to about 44%), as compared to a reference level. In some embodiments, a level of CD8+GzB+ T cells in a sample (e.g., blood) from the subject is increased by about 6% to about 18% (e.g., about 6% to about 12%, about 9% to about 14%, or about 12% to about 18%), as compared to a reference level. In some embodiments, a level of CD8+KI67+ T cells in a sample (e.g., blood) from the subject is increased by about 22% to about 67% (e.g., about 22% to about 45%, about 34% to about 50%, or about 45% to about 67%), as compared to a reference level. In some embodiments, a level of CD8+PD1 + T cells in a sample (e.g., blood) from the subject is increased by about 9% to about 26% (e.g., about 9% to about 18%, about 13% to about 20%, or about 18% to about 26%), as compared to a reference level. In some embodiments, a level of CD8+PD1 + T cells in a sample (e.g., blood) from the subject is increased by about 8% to about 24% (e.g., about 8% to about 16%, about 12% to about 18%, or about 16% to about 24%), as compared to a reference level. In some embodiments, a level of CD8+PD1 +GzB+ T cells in a sample (e.g., blood) from the subject is increased by about 1 1 % to about 34% (e.g., about 1 1 % to about 23%, about 17% to about 26%, or about 23% to about 34%), as compared to a reference level. In some embodiments, a level of CD8+PD1 +KI67+ T cells in a sample (e.g., blood) from the subject is increased by about 26% to about 78% (e.g., about 26% to about 52%, about 39% to about 59%, or about 52% to about 78%), as compared to a reference level. In some embodiments, a level of CD8+DR+ TCM cells in a sample (e.g., blood) from the subject is increased by about 14% to about 43% (e.g., about 14% to about 28%, about 21 % to about 32%, or about 28% to about 43%), as compared to a reference level. In some embodiments, a level of CD8+DR+GzB+ TCM cells in a sample (e.g., blood) from the subject is increased by about 20% to about 61 % (e.g., about 20% to about 41 %, about 31 % to about 46%, or about 41 % to about 61 %), as compared to a reference level. In some embodiments, a level of CD8+DR+KI67+ TCM cells in a sample (e.g., blood) from the subject is increased by about 18% to about 54% (e.g., about 18% to about 36%, about 27% to about 40%, or about 36% to about 54%), as compared to a reference level. In some embodiments, a level of CD8+DR+PD1 + TCM cells in a sample (e.g., blood) from the subject is increased by about 17% to about 51 % (e.g., about 17% to about 34%, about 25% to about 38%, or about 34% to about 51 %), as compared to a reference level. In some embodiments, a level of CD8+GzB+ TCM cells in a sample (e.g., blood) from the subject is increased by about 18% to about 55% (e.g., about 18% to about 37%, about 27% to about 41 %, or about 37% to about 55%), as compared to a reference level. In some embodiments, a level of CD8+KI67+ TCM cells in a sample (e.g., blood) from the subject is increased by about 16% to about 49% (e.g., about 16% to about 33%, about 25% to about 37%, or about 33% to about 49%), as compared to a reference level. In some embodiments, a level of CD8+PD1 + TCM cells in a sample (e.g., blood) from the subject is increased by about 11% to about 34% (e.g., about 11% to about 23%, about 17% to about 25%, or about 23% to about 34%), as compared to a reference level. In some embodiments, a level of CD8+PD1 +0X40+ TCM cells in a sample (e.g., blood) from the subject is increased by about 14% to about 43% (e.g., about 14% to about 28%, about 21 % to about 32%, or about 28% to about 43%), as compared to a reference level. In some embodiments, a level of CD8+DR+ TEM cells in a sample (e.g., blood) from the subject is increased by about 7% to about 22% (e.g., about 7% to about 15%, about 11 % to about 17%, or about 15% to about 22%), as compared to a reference level. In some embodiments, a level of CD8+DR+GzB+ TEM cells in a sample (e.g., blood) from the subject is increased by about 8% to about 24% (e.g., about 8% to about 16%, about 12% to about 18%, or about 16% to about 24%), as compared to a reference level. In some embodiments, a level of CD8+DR+KI67+ TEM cells in a sample (e.g., blood) from the subject is increased by about 18% to about 55% (e.g., about 18% to about 36%, about 27% to about 41 %, or about 36% to about 55%), as compared to a reference level. In some embodiments, a level of CD8+DR+PD1 + TEM cells in a sample (e.g., blood) from the subject is increased by about 11% to about 34% (e.g., about 11 % to about 23%, about 17% to about 26%, or about 23% to about 34%), as compared to a reference level. In some embodiments, a level of CD8+GzB+ TEM cells in a sample (e.g., blood) from the subject is increased by about 6% to about 17% (e.g., about 6% to about 11%, about 8% to about 13%, or about 11 % to about 17%), as compared to a reference level. In some embodiments, a level of CD8+KI67+ TEM cells in a sample (e.g., blood) from the subject is increased by about 16% to about 47% (e.g., about 16% to about 31 %, about 23% to about 35%, or about 31 % to about 47%), as compared to a reference level. In some embodiments, a level of CD8+PD1 + TEM cells in a sample (e.g., blood) from the subject is increased by about 6% to about 18% (e.g., about 6% to about 12%, about 9% to about 14%, or about 12% to about 18%), as compared to a reference level. In some embodiments, a level of CD8+DR+ TEMRA cells in a sample (e.g., blood) from the subject is increased by about 5% to about 16% (e.g., about 5% to about 11%, about 8% to about 12%, or about 11% to about 16%), as compared to a reference level. In some embodiments, a level of CD8+DR+KI67+ TEMRA cells in a sample (e.g., blood) from the subject is increased by about 23% to about 69% (e.g., about 23% to about 46%, about 34% to about 52%, or about 46% to about 69%), as compared to a reference level. In some embodiments, a level of CD8+DR+PD1 + TEMRA cells in a sample (e.g., blood) from the subject is increased by about 11% to about 34% (e.g., about 11% to about 23%, about 17% to about 26%, or about 23% to about 34%), as compared to a reference level. In some embodiments, a level of CD8+GzB+ TEMRA cells in a sample (e.g., blood) from the subject is increased by about 3% to about 8% (e.g., about 3% to about 5%, about 4% to about 6%, or about 5% to about 8%), as compared to a reference level. In some embodiments, a level of CD8+KI67+ TEMRA cells in a sample (e.g., blood) from the subject is increased by about 22% to about 65% (e.g., about 22% to about 43%, about 32% to about 48%, or about 43% to about 65%), as compared to a reference level. In some embodiments, a level of CD8+PD1 + TEMRA cells in a sample (e.g., blood) from the subject is increased by about 7% to about 21% (e.g., about 7% to about 14%, about 11% to about 16%, or about 14% to about 21%), as compared to a reference level. In some embodiments, a level of CD8+DR+ TN cells in a sample (e.g., blood) from the subject is increased by about 15% to about 46% (e.g., about 15% to about 31%, about 23% to about 35%, or about 31% to about 46%), as compared to a reference level. In some embodiments, a level of CD8+DR+GzB+ TN cells in a sample (e.g., blood) from the subject is increased by about 27% to about 80% (e.g., about 27% to about 53%, about 40% to about 60%, or about 53% to about 80%), as compared to a reference level. In some embodiments, a level of CD8+DR+KI67+ TN cells in a sample (e.g., blood) from the subject is increased by about 39% to about 116% (e.g., about 39% to about 77%, about 58% to about 87%, or about 77% to about 116%), as compared to a reference level. In some embodiments, a level of CD8+DR+PD1 + TN cells in a sample (e.g., blood) from the subject is increased by about 27% to about 82% (e.g., about 27% to about 54%, about 41 % to about 61%, or about 54% to about 82%), as compared to a reference level. In some embodiments, a level of CD8+GzB+ TN cells in a sample (e.g., blood) from the subject is increased by about 23% to about 69% (e.g., about 23% to about 46%, about 34% to about 52%, or about 46% to about 69%), as compared to a reference level. In some embodiments, a level of CD8+KI67+ TN cells in a sample (e.g., blood) from the subject is increased by about 34% to about 103% (e.g., about 34% to about 69%, about 51% to about 77%, or about 69% to about 103%), as compared to a reference level. In some embodiments, a level of CD8+PD1 + TN cells in a sample (e.g., blood) from the subject is increased by about 11 % to about 32% (e.g., about 11 % to about 21 %, about 16% to about 24%, or about 21 % to about 32%), as compared to a reference level. In some embodiments, a level of CD8+PD1 +OX40+ TN cells in a sample (e.g., blood) from the subject is increased by about 12% to about 37% (e.g., about 12% to about 25%, about 18% to about 28%, or about 25% to about 37%), as compared to a reference level. In some embodiments, a level of CD3-DR+ cells in a sample (e.g., blood) from the subject is increased by about 8% to about 23% (e.g., about 8% to about 15%, about 11 % to about 17%, or about 15% to about 23%), as compared to a reference level. In some embodiments, a level of 0X40+ Treg cells in a sample (e.g., blood) from the subject is increased by about 9% to about 28% (e.g., about 9% to about 19%, about 14% to about 21%, or about 19% to about 28%), as compared to a reference level. In some embodiments, a level of PD1 +OX40+ Treg cells in a sample (e.g., blood) from the subject is increased by about 13% to about 38% (e.g., about 13% to about 25%, about 19% to about 29%, or about 25% to about 38%), as compared to a reference level. In some embodiments, a level of true NK cells in a sample (e.g., blood) from the subject is increased by about 6% to about 18% (e.g., about 6% to about 12%, about 9% to about 13%, or about 12% to about 18%), as compared to a reference level. In some embodiments, a level of white blood cells in a sample (e.g., blood) from the subject is increased by about 2% to about 5% (e.g., about 2% to about 3%, about 3% to about 4%, or about 3% to about 5%), as compared to a reference level. In some embodiments, a level of white blood cells in a sample (e.g., blood) from the subject is increased by about 2% to about 5% (e.g., about 2% to about 3%, about 2% to about 4%, or about 3% to about 5%), as compared to a reference level. In some embodiments, a level of white blood cells in a sample (e.g., blood) from the subject is increased by about 2% to about 7% (e.g., about 2% to about 5%, about 3% to about 5%, or about 5% to about 7%), as compared to a reference level. In some embodiments, a level of white blood cells in a sample (e.g., blood) from the subject is increased by about 2% to about 5% (e.g., about 2% to about 4%, about 3% to about 4%, or about 4% to about 5%), as compared to a reference level.

Table 8. Cell Types in Blood that are Associated with Increased Resistance to Cevostamab

CD = cluster of differentiation; DR = human leukocyte antigen - DR isotype; Ki67 = antigen Kiel 67; PD1 = programmed cell death protein 1 ; GzB = Granzyme B; TIGIT = T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains; TIM3 = T cell immunoglobulin and mucin-domain containing-3; TN cells = naive T cells; TCM cells = central memory T cells; TEM cells = effector memory T cells; TEMRA cells = terminally differentiated effector memory T cells; Treg cells = regulatory T cells; NK cells = natural killer cells Conversely, MM subjects having a decreased level (e.g., presence or percentage) of one or more (e.g., one, two, three, four, five, six, seven, eight, nine, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, or all 80) cell types set forth in Table 8 in a blood sample (e.g., a baseline blood sample), as compared to a reference level, are generally more sensitive to treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab). For example, in some embodiments, a level of CD8+DR+ TCM cells in a sample (e.g., bone marrow) from the subject is decreased by about 6% to about 17% (e.g., about 6% to about 12%, about 9% to about 13%, or about 12% to about 17%), as compared to a reference level. In some embodiments, a level of CD4+DR+ T cells in a sample (e.g., blood) from the subject is decreased by about 8% to about 23% (e.g., about 8% to about 15%, about 1 1 % to about 17%, or about 15% to about 23%), as compared to a reference level. In some embodiments, a level of CD4+DR+GzB+ T cells in a sample (e.g., blood) from the subject is decreased by about 7% to about 20% (e.g., about 7% to about 14%, about 10% to about 15%, or about 14% to about 20%), as compared to a reference level. In some embodiments, a level of CD4+DR+KI67+ T cells in a sample (e.g., blood) from the subject is decreased by about 10% to about 29% (e.g., about 10% to about 19%, about 15% to about 22%, or about 19% to about 29%), as compared to a reference level. In some embodiments, a level of CD4+DR+PD1 + T cells in a sample (e.g., blood) from the subject is decreased by about 1 1 % to about 32% (e.g., about 1 1 % to about 21 %, about 16% to about 24%, or about 21 % to about 32%), as compared to a reference level. In some embodiments, a level of CD4+KI67+ T cells in a sample (e.g., blood) from the subject is decreased by about 9% to about 26% (e.g., about 9% to about 17%, about 13% to about 19%, or about 17% to about 26%), as compared to a reference level. In some embodiments, a level of CD4+PD1 + T cells in a sample (e.g., blood) from the subject is decreased by about 5% to about 15% (e.g., about 5% to about 10%, about 8% to about 1 1 %, or about 10% to about 15%), as compared to a reference level. In some embodiments, a level of CD4+PD1 + T cells in a sample (e.g., blood) from the subject is decreased by about 5% to about 16% (e.g., about 5% to about 1 1 %, about 8% to about 12%, or about 1 1 % to about 16%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +KI67+ T cells in a sample (e.g., blood) from the subject is decreased by about 10% to about 31 % (e.g., about 10% to about 21 %, about 15% to about 23%, or about 21 % to about 31 %), as compared to a reference level. In some embodiments, a level of CD4+PD1 +OX40- T cells in a sample (e.g., blood) from the subject is decreased by about 2% to about 6% (e.g., about 2% to about 4%, about 3% to about 4%, or about 4% to about 6%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +OX40+ T cells in a sample (e.g., blood) from the subject is decreased by about 5% to about 14% (e.g., about 5% to about 9%, about 7% to about 10%, or about 9% to about 14%), as compared to a reference level. In some embodiments, a level of CD4+PD1 - TIGIT+TIM3- T cells in a sample (e.g., blood) from the subject is decreased by about 5% to about 14% (e.g., about 5% to about 9%, about 7% to about 10%, or about 9% to about 14%), as compared to a reference level. In some embodiments, a level of CD4+PDL1 + T cells in a sample (e.g., blood) from the subject is decreased by about 6% to about 18% (e.g., about 6% to about 12%, about 9% to about 13%, or about 12% to about 18%), as compared to a reference level. In some embodiments, a level of CD4+TIGIT+ T cells in a sample (e.g., blood) from the subject is decreased by about 5% to about 14% (e.g., about 5% to about 9%, about 7% to about 10%, or about 9% to about 14%), as compared to a reference level. In some embodiments, a level of CD4+DR+ TCM cells in a sample (e.g., blood) from the subject is decreased by about 10% to about 31 % (e.g., about 10% to about 21 %, about 15% to about 23%, or about 21 % to about 31 %), as compared to a reference level. In some embodiments, a level of CD4+DR+KI67+ TCM cells in a sample (e.g., blood) from the subject is decreased by about 10% to about 29% (e.g., about 10% to about 20%, about 15% to about 22%, or about 20% to about 29%), as compared to a reference level. In some embodiments, a level of CD4+DR+PD1 + TCM cells in a sample (e.g., blood) from the subject is decreased by about 14% to about 41 % (e.g., about 14% to about 27%, about 20% to about 30%, or about 27% to about 41 %), as compared to a reference level. In some embodiments, a level of CD4+KI67+ TCM cells in a sample (e.g., blood) from the subject is decreased by about 8% to about 23% (e.g., about 8% to about 15%, about 1 1 % to about 17%, or about 15% to about 23%), as compared to a reference level. In some embodiments, a level of CD4+PD1 + TCM cells in a sample (e.g., blood) from the subject is decreased by about 6% to about 19% (e.g., about 6% to about 12%, about 9% to about 14%, or about 12% to about 19%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +OX40+ TCM cells in a sample (e.g., blood) from the subject is decreased by about 5% to about 15% (e.g., about 5% to about 10%, about 7% to about 1 1 %, or about 10% to about 15%), as compared to a reference level. In some embodiments, a level of CD4+DR+ TEM cells in a sample (e.g., blood) from the subject is decreased by about 5% to about 15% (e.g., about 5% to about 10%, about 8% to about 1 1 %, or about 10% to about 15%), as compared to a reference level. In some embodiments, a level of CD4+DR+KI67+ TEM cells in a sample (e.g., blood) from the subject is decreased by about 8% to about 23% (e.g., about 8% to about 15%, about 1 1 % to about 17%, or about 15% to about 23%), as compared to a reference level. In some embodiments, a level of CD4+DR+PD1 + TEM cells in a sample (e.g., blood) from the subject is decreased by about 7% to about 21 % (e.g., about 7% to about 14%, about 1 1 % to about 16%, or about 14% to about 21 %), as compared to a reference level. In some embodiments, a level of CD4+KI67+ TEM cells in a sample (e.g., blood) from the subject is decreased by about 7% to about 21 % (e.g., about 7% to about 14%, about 1 1 % to about 16%, or about 14% to about 21 %), as compared to a reference level. In some embodiments, a level of CD4+PD1 + TEM cells in a sample (e.g., blood) from the subject is decreased by about 3% to about 10% (e.g., about 3% to about 6%, about 5% to about 7%, or about 6% to about 10%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +OX40+ TEM cells in a sample (e.g., blood) from the subject is decreased by about 3% to about 9% (e.g., about 3% to about 6%, about 5% to about 7%, or about 6% to about 9%), as compared to a reference level. In some embodiments, a level of CD4+DR+ TEMRA cells in a sample (e.g., blood) from the subject is decreased by about 6% to about 18% (e.g., about 6% to about 12%, about 9% to about 14%, or about 12% to about 18%), as compared to a reference level. In some embodiments, a level of CD4+DR+GzB+ TEMRA cells in a sample (e.g., blood) from the subject is decreased by about 5% to about 16% (e.g., about 5% to about 11 %, about 8% to about 12%, or about 11 % to about 16%), as compared to a reference level. In some embodiments, a level of CD4+DR+KI67+ TEMRA cells in a sample (e.g., blood) from the subject is decreased by about 9% to about 27% (e.g., about 9% to about 18%, about 14% to about 20%, or about 18% to about 27%), as compared to a reference level. In some embodiments, a level of CD4+DR+PD1 + TEMRA cells in a sample (e.g., blood) from the subject is decreased by about 8% to about 25% (e.g., about 8% to about 17%, about 13% to about 19%, or about 17% to about 25%), as compared to a reference level. In some embodiments, a level of CD4+KI67+ TEMRA cells in a sample (e.g., blood) from the subject is decreased by about 8% to about 25% (e.g., about 8% to about 17%, about 13% to about 19%, or about 17% to about 25%), as compared to a reference level. In some embodiments, a level of CD4+PD1 + TEMRA cells in a sample (e.g., blood) from the subject is decreased by about 4% to about 11% (e.g., about 4% to about 7%, about 6% to about 8%, or about 7% to about 11%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +OX40+ TEMRA cells in a sample (e.g., blood) from the subject is decreased by about 4% to about 12% (e.g., about 4% to about 8%, about 6% to about 9%, or about 8% to about 12%), as compared to a reference level. In some embodiments, a level of CD4+DR+ TN cells in a sample (e.g., blood) from the subject is decreased by about 8% to about 23% (e.g., about 8% to about 16%, about 12% to about 17%, or about 16% to about 23%), as compared to a reference level. In some embodiments, a level of CD4+DR+KI67+ TN cells in a sample (e.g., blood) from the subject is decreased by about 15% to about 45% (e.g., about 15% to about 30%, about 23% to about 34%, or about 30% to about 45%), as compared to a reference level. In some embodiments, a level of CD4+DR+PD1 + TN cells in a sample (e.g., blood) from the subject is decreased by about 21 % to about 64% (e.g., about 21% to about 43%, about 32% to about 48%, or about 43% to about 64%), as compared to a reference level. In some embodiments, a level of CD4+KI67+ TN cells in a sample (e.g., blood) from the subject is decreased by about 11% to about 32% (e.g., about 11% to about 22%, about 16% to about 24%, or about 22% to about 32%), as compared to a reference level. In some embodiments, a level of CD4+PD1 + TN cells in a sample (e.g., blood) from the subject is decreased by about 8% to about 23% (e.g., about 8% to about 15%, about 12% to about 17%, or about 15% to about 23%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +OX40+ TN cells in a sample (e.g., blood) from the subject is decreased by about 7% to about 22% (e.g., about 7% to about 14%, about 11% to about 16%, or about 14% to about 22%), as compared to a reference level. In some embodiments, a level of CD8+DR+ T cells in a sample (e.g., blood) from the subject is decreased by about 3% to about 10% (e.g., about 3% to about 7%, about 5% to about 8%, or about 7% to about 10%), as compared to a reference level. In some embodiments, a level of CD8+DR+GzB+ T cells in a sample (e.g., blood) from the subject is decreased by about 4% to about 11% (e.g., about 4% to about 7%, about 5% to about 8%, or about 7% to about 11%), as compared to a reference level. In some embodiments, a level of

CD8+DR+KI67+ T cells in a sample (e.g., blood) from the subject is decreased by about 10% to about 30% (e.g., about 10% to about 20%, about 15% to about 22%, or about 20% to about 30%), as compared to a reference level. In some embodiments, a level of CD8+DR+PD1 + T cells in a sample (e.g., blood) from the subject is decreased by about 6% to about 17% (e.g., about 6% to about 12%, about 9% to about 13%, or about 12% to about 17%), as compared to a reference level. In some embodiments, a level of CD8+GzB+ T cells in a sample (e.g., blood) from the subject is decreased by about 2% to about 7% (e.g., about 2% to about 5%, about 4% to about 6%, or about 5% to about 7%), as compared to a reference level. In some embodiments, a level of CD8+KI67+ T cells in a sample (e.g., blood) from the subject is decreased by about 9% to about 27% (e.g., about 9% to about 18%, about 13% to about 20%, or about 18% to about 27%), as compared to a reference level. In some embodiments, a level of CD8+PD1 + T cells in a sample (e.g., blood) from the subject is decreased by about 4% to about 1 1 % (e.g., about 4% to about 7%, about 5% to about 8%, or about 7% to about 1 1 %), as compared to a reference level. In some embodiments, a level of CD8+PD1 + T cells in a sample (e.g., blood) from the subject is decreased by about 3% to about 10% (e.g., about 3% to about 6%, about 5% to about 7%, or about 6% to about 10%), as compared to a reference level. In some embodiments, a level of CD8+PD1 +GzB+ T cells in a sample (e.g., blood) from the subject is decreased by about 5% to about 14% (e.g., about 5% to about 9%, about 7% to about 10%, or about 9% to about 14%), as compared to a reference level. In some embodiments, a level of CD8+PD1 +KI67+ T cells in a sample (e.g., blood) from the subject is decreased by about 10% to about 31 % (e.g., about 10% to about 21 %, about 16% to about 23%, or about 21 % to about 31 %), as compared to a reference level. In some embodiments, a level of CD8+DR+ TCM cells in a sample (e.g., blood) from the subject is decreased by about 6% to about 17% (e.g., about 6% to about 1 1 %, about 8% to about 13%, or about 1 1 % to about 17%), as compared to a reference level. In some embodiments, a level of CD8+DR+GzB+ TCM cells in a sample (e.g., blood) from the subject is decreased by about 8% to about 25% (e.g., about 8% to about 16%, about 12% to about 18%, or about 16% to about 25%), as compared to a reference level. In some embodiments, a level of CD8+DR+KI67+ TCM cells in a sample (e.g., blood) from the subject is decreased by about 7% to about 21 % (e.g., about 7% to about 14%, about 1 1 % to about 16%, or about 14% to about 21 %), as compared to a reference level. In some embodiments, a level of CD8+DR+PD1 + TCM cells in a sample (e.g., blood) from the subject is decreased by about 7% to about 20% (e.g., about 7% to about 14%, about 10% to about 15%, or about 14% to about 20%), as compared to a reference level. In some embodiments, a level of CD8+GzB+ TCM cells in a sample (e.g., blood) from the subject is decreased by about 7% to about 22% (e.g., about 7% to about 15%, about 1 1 % to about 16%, or about 15% to about 22%), as compared to a reference level. In some embodiments, a level of CD8+KI67+ TCM cells in a sample (e.g., blood) from the subject is decreased by about 7% to about 20% (e.g., about 7% to about 13%, about 10% to about 15%, or about 13% to about 20%), as compared to a reference level. In some embodiments, a level of CD8+PD1 + TCM cells in a sample (e.g., blood) from the subject is decreased by about 4% to about 13% (e.g., about 4% to about 9%, about 7% to about 10%, or about 9% to about 13%), as compared to a reference level. In some embodiments, a level of CD8+PD1 +0X40+ TCM cells in a sample (e.g., blood) from the subject is decreased by about 6% to about 17% (e.g., about 6% to about 1 1 %, about 9% to about 13%, or about 11% to about 17%), as compared to a reference level. In some embodiments, a level of CD8+DR+ TEM cells in a sample (e.g., blood) from the subject is decreased by about 3% to about 9% (e.g., about 3% to about 6%, about 4% to about 7%, or about 6% to about 9%), as compared to a reference level. In some embodiments, a level of CD8+DR+GzB+ TEM cells in a sample (e.g., blood) from the subject is decreased by about 3% to about 10% (e.g., about 3% to about 6%, about 5% to about 7%, or about 6% to about 10%), as compared to a reference level. In some embodiments, a level of CD8+DR+KI67+ TEM cells in a sample (e.g., blood) from the subject is decreased by about 7% to about 22% (e.g., about 7% to about 15%, about 11 % to about 16%, or about 15% to about 22%), as compared to a reference level. In some embodiments, a level of CD8+DR+PD1 + TEM cells in a sample (e.g., blood) from the subject is decreased by about 5% to about 14% (e.g., about 5% to about 9%, about 7% to about 10%, or about 9% to about 14%), as compared to a reference level. In some embodiments, a level of CD8+GzB+ TEM cells in a sample (e.g., blood) from the subject is decreased by about 2% to about 7% (e.g., about 2% to about 4%, about 3% to about 5%, or about 4% to about 7%), as compared to a reference level. In some embodiments, a level of CD8+KI67+ TEM cells in a sample (e.g., blood) from the subject is decreased by about 6% to about 19% (e.g., about 6% to about 12%, about 9% to about 14%, or about 12% to about 19%), as compared to a reference level. In some embodiments, a level of CD8+PD1 + TEM cells in a sample (e.g., blood) from the subject is decreased by about 2% to about 7% (e.g., about 2% to about 5%, about 4% to about 5%, or about 5% to about 7%), as compared to a reference level. In some embodiments, a level of CD8+DR+ TEMRA cells in a sample (e.g., blood) from the subject is decreased by about 2% to about 7% (e.g., about 2% to about 4%, about 3% to about 5%, or about 4% to about 7%), as compared to a reference level. In some embodiments, a level of CD8+DR+KI67+ TEMRA cells in a sample (e.g., blood) from the subject is decreased by about 9% to about 27% (e.g., about 9% to about 18%, about 14% to about 21%, or about 18% to about 27%), as compared to a reference level. In some embodiments, a level of CD8+DR+PD1 + TEMRA cells in a sample (e.g., blood) from the subject is decreased by about 5% to about 14% (e.g., about 5% to about 9%, about 7% to about 10%, or about 9% to about 14%), as compared to a reference level. In some embodiments, a level of CD8+GzB+ TEMRA cells in a sample (e.g., blood) from the subject is decreased by about 1% to about 3% (e.g., about 1% to about 2%, about 2% to about 2%, or about 2% to about 3%), as compared to a reference level. In some embodiments, a level of CD8+KI67+ TEMRA cells in a sample (e.g., blood) from the subject is decreased by about 9% to about 26% (e.g., about 9% to about 17%, about 13% to about 19%, or about 17% to about 26%), as compared to a reference level. In some embodiments, a level of CD8+PD1 + TEMRA cells in a sample (e.g., blood) from the subject is decreased by about 3% to about 9% (e.g., about 3% to about 6%, about 4% to about 6%, or about 6% to about 9%), as compared to a reference level. In some embodiments, a level of CD8+DR+ TN cells in a sample (e.g., blood) from the subject is decreased by about 6% to about 18% (e.g., about 6% to about 12%, about 9% to about 14%, or about 12% to about 18%), as compared to a reference level. In some embodiments, a level of CD8+DR+GzB+ TN cells in a sample (e.g., blood) from the subject is decreased by about 11% to about 32% (e.g., about 11% to about 21%, about 16% to about 24%, or about 21 % to about 32%), as compared to a reference level. In some embodiments, a level of CD8+DR+KI67+ TN cells in a sample (e.g., blood) from the subject is decreased by about 15% to about 46% (e.g., about 15% to about 31 %, about 23% to about 35%, or about 31 % to about 46%), as compared to a reference level. In some embodiments, a level of CD8+DR+PD1 + TN cells in a sample (e.g., blood) from the subject is decreased by about 1 1 % to about 33% (e.g., about 1 1 % to about 22%, about 16% to about 24%, or about 22% to about 33%), as compared to a reference level. In some embodiments, a level of CD8+GzB+ TN cells in a sample (e.g., blood) from the subject is decreased by about 9% to about 27% (e.g., about 9% to about 18%, about 14% to about 21 %, or about 18% to about 27%), as compared to a reference level. In some embodiments, a level of CD8+KI67+ TN cells in a sample (e.g., blood) from the subject is decreased by about 14% to about 41 % (e.g., about 14% to about 27%, about 21 % to about 31 %, or about 27% to about 41 %), as compared to a reference level. In some embodiments, a level of CD8+PD1 + TN cells in a sample (e.g., blood) from the subject is decreased by about 4% to about 13% (e.g., about 4% to about 8%, about 6% to about 10%, or about 8% to about 13%), as compared to a reference level. In some embodiments, a level of CD8+PD1 +0X40+ TN cells in a sample (e.g., blood) from the subject is decreased by about 5% to about 15% (e.g., about 5% to about 10%, about 7% to about 1 1 %, or about 10% to about 15%), as compared to a reference level. In some embodiments, a level of CD3-DR+ cells in a sample (e.g., blood) from the subject is decreased by about 3% to about 9% (e.g., about 3% to about 6%, about 5% to about 7%, or about 6% to about 9%), as compared to a reference level. In some embodiments, a level of 0X40+ Treg cells in a sample (e.g., blood) from the subject is decreased by about 4% to about 1 1 % (e.g., about 4% to about 7%, about 6% to about 8%, or about 7% to about 1 1 %), as compared to a reference level. In some embodiments, a level of PD1 +OX40+ Treg cells in a sample (e.g., blood) from the subject is decreased by about 5% to about 15% (e.g., about 5% to about 10%, about 8% to about 1 1 %, or about 10% to about 15%), as compared to a reference level. In some embodiments, a level of true NK cells in a sample (e.g., blood) from the subject is decreased by about 2% to about 7% (e.g., about 2% to about 5%, about 4% to about 5%, or about 5% to about 7%), as compared to a reference level. In some embodiments, a level of white blood cells in a sample (e.g., blood) from the subject is decreased by about 1 % to about 3%, as compared to a reference level.

Cell types in blood that are associated with increased sensitivity to cevostamab In some aspects of the invention, the methods described herein require determining a level of one or more cell types set forth in Table 9 in the blood (e.g., whole blood, serum, or plasma) of the subject. In some aspects of the invention, the methods described herein require that a level of one or more cell types set forth in Table 9 has been previously determined in the blood of the subject.

In general, MM subjects having an increased level (e.g., presence or percentage) of one or more (e.g., one, two, three, four, or all five) cell types set forth in Table 9, as compared to a reference level, are more sensitive to treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab). For example, in some embodiments, a level of CD4+ T cells in a sample (e.g., blood) from the subject is increased by about 4% to about 11% (e.g., about 4% to about 7%, about 6% to about 8%, or about 7% to about 11%), as compared to a reference level. In some embodiments, a level of CD4+ T cells in a sample (e.g., blood) from the subject is increased by about 2% to about 7% (e.g., about 2% to about 5%, about 4% to about 6%, or about 5% to about 7%), as compared to a reference level. In some embodiments, a level of CD4+ T cells in a sample (e.g., blood) from the subject is increased by about 4% to about 11% (e.g., about 4% to about 7%, about 5% to about 8%, or about 7% to about 11%), as compared to a reference level. In some embodiments, a level of CD4+ T cells in a sample (e.g., blood) from the subject is increased by about 4% to about 12% (e.g., about 4% to about 8%, about 6% to about 9%, or about 8% to about 12%), as compared to a reference level. In some embodiments, a level of CD8+CD25+CD69- T cells in a sample (e.g., blood) from the subject is increased by about 9% to about 28% (e.g., about 9% to about 18%, about 14% to about 21%, or about 18% to about 28%), as compared to a reference level. In some embodiments, a level of CD8+NK T cells in a sample (e.g., blood) from the subject is increased by about 2% to about 6% (e.g., about 2% to about 4%, about 3% to about 5%, or about 4% to about 6%), as compared to a reference level. In some embodiments, a level of CD8+ TCM cells in a sample (e.g., blood) from the subject is increased by about 7% to about 20% (e.g., about 7% to about 13%, about 10% to about 15%, or about 13% to about 20%), as compared to a reference level. In some embodiments, a level of CD8+ TN cells in a sample (e.g., blood) from the subject is increased by about 5% to about 16% (e.g., about 5% to about 11 %, about 8% to about 12%, or about 11 % to about 16%), as compared to a reference level. In some embodiments, a level of CD8+ TN cells in a sample (e.g., blood) from the subject is increased by about 6% to about 17% (e.g., about 6% to about 11%, about 8% to about 13%, or about 11% to about 17%), as compared to a reference level.

Table 9. Cell Types in Blood that are Associated with Increased Sensitivity to Cevostamab

_

CD = cluster of differentiation; NK T cells = natural killer T cells; TN cells = naive T cells; TCM cells = central memory T cells

Conversely, MM subjects having a decreased level (e.g., presence or percentage) of one or more (e.g., one, two, three, four, or all five) cell types set forth in Table 9, as compared to a reference level, are more resistant to treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab). For example, in some embodiments, a level of CD4+ T cells in a sample (e.g., blood) from the subject is decreased by about 9% to about 28% (e.g., about 9% to about 19%, about 14% to about 21 %, or about 19% to about 28%), as compared to a reference level. In some embodiments, a level of CD4+ T cells in a sample (e.g., blood) from the subject is decreased by about 6% to about 19% (e.g., about 6% to about 12%, about 9% to about 14%, or about 12% to about 19%), as compared to a reference level. In some embodiments, a level of CD4+ T cells in a sample (e.g., blood) from the subject is decreased by about 9% to about 27% (e.g., about 9% to about 18%, about 13% to about 20%, or about 18% to about 27%), as compared to a reference level. In some embodiments, a level of CD4+ T cells in a sample (e.g., blood) from the subject is decreased by about 10% to about 30% (e.g., about 10% to about 20%, about 15% to about 22%, or about 20% to about 30%), as compared to a reference level. In some embodiments, a level of CD8+CD25+CD69- T cells in a sample (e.g., blood) from the subject is decreased by about 23% to about 69% (e.g., about 23% to about 46%, about 35% to about 52%, or about 46% to about 69%), as compared to a reference level. In some embodiments, a level of CD8+NK T cells in a sample (e.g., blood) from the subject is decreased by about 5% to about 15% (e.g., about 5% to about 10%, about 8% to about 1 1 %, or about 10% to about 15%), as compared to a reference level. In some embodiments, a level of CD8+ TCM cells in a sample (e.g., blood) from the subject is decreased by about 16% to about 49% (e.g., about 16% to about 33%, about 25% to about 37%, or about 33% to about 49%), as compared to a reference level. In some embodiments, a level of CD8+ TN cells in a sample (e.g., blood) from the subject is decreased by about 13% to about 40% (e.g., about 13% to about 26%, about 20% to about 30%, or about 26% to about 40%), as compared to a reference level. In some embodiments, a level of CD8+ TN cells in a sample (e.g., blood) from the subject is decreased by about 14% to about 42% (e.g., about 14% to about 28%, about 21 % to about 32%, or about 28% to about 42%), as compared to a reference level.

A. Methods of treating

In some aspects, the invention provides a method of treating a subject having an MM. The method may include administering to the subject a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab). Prior to the administering of the bispecific antibody, a sample from the subject may have been previously determined to have a decreased level of one or more cell types set forth in Table 3, Table 6, and/or Table 8, as compared to a reference level. Prior to the administering of the bispecific antibody, a sample from the subject may have been previously determined to have an increased level of one or more cell types set forth in Table 4, Table 7, and/or Table 9, as compared to a reference level. The sample from the subject may be from the subject’s bone marrow and/or blood. Prior to the administering of the bispecific antibody, the subject may have been previously determined to have lower number in one or more of the features set forth in Table 5, as compared to a reference number. In some aspects, the reference level is an assigned reference level set forth in Table 14. In some aspects, the reference number is an assigned reference number set forth in Table 15.

Flow cytometry (FC), mass spectrometry (MS), immunohistochemistry (IHC), DNA sequencing (DNA-seq), RNA sequencing (RNA-seq), quantitative PCR (qPCR), reverse transcription- quantitative polymerase chain reaction (RT-qPCR), multiplex qPCR or RT-qPCR, microarray analysis, serial analysis of gene expression (SAGE), MASSARRAY® technique, in situ hybridization (ISH), or a combination thereof, may be used to determine the level of one or more cell types in a sample (e.g., BM or blood).

Prior to the administering of the bispecific antibody, a sample from the subject’s bone marrow may have been previously determined to have a decreased level of one or more cell types set forth in Table 3 and/or Table 6, as compared to a reference level. Prior to the administering of the bispecific antibody, a sample from the subject’s bone marrow may have been previously determined to have an increased level of one or more cell types set forth in Table 4 and/or Table 7, as compared to a reference level.

Prior to the administering of the bispecific antibody, a sample from the subject’s blood (e.g., whole blood, plasma, or serum) may have been previously determined to have a decreased level of one or more cell types set forth in Table 3 and/or Table 8, as compared to a reference level. Prior to the administering of the bispecific antibody, a sample from the subject’s blood (e.g., whole blood, plasma, or serum) may have been previously determined to have an increased level of one or more cell types set forth in Table 4 and/or Table 9, as compared to a reference level.

In some aspects, the invention provides a method of treating a subject having an MM, wherein the method may optionally include a step of determining a level of one or more cell types set forth in Table 3 and/or Table 4 in a sample from the subject. The sample from the subject may be from the subject’s bone marrow and/or blood. In some aspects of the invention, the method may or may not include a step of determining one or more of the features set forth in Table 5.

The method of treating the subject having an MM may include a step of identifying the subject as one who would benefit from a treatment comprising a bispecific antibody that binds to FcRH5 and CD3 prior to administering the bispecific antibody. A subject may benefit from the treatment based on a relative increase in overall survival (OS), objective response rate (ORR), progression-free survival (PFS), complete response (CR), partial response (PR), or a combination thereof.

A subject that has a decreased level of the one or more cell types set forth in Table 3, as compared to a reference level, an increased level of the one or more cell types set forth in Table 4, as compared to a reference level, and/or a lower number in one or more of the features set forth in Table 5, as compared to a reference number, may be identified as one who would benefit from the treatment comprising the bispecific antibody that binds to FcRH5 and CD3. The method of treating the subject having an MM may further include a step of administering to the identified subject the treatment comprising the bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab).

In some aspects of the invention, the sample is from the subject’s bone marrow and has a decreased level of one or more cell types set forth in Table 3 and/or Table 6, as compared to a reference level. In some aspects of the invention, the sample is from the subject’s bone marrow and has an increased level of one or more cell types set forth in Table 4 and/or Table 7, as compared to a reference level.

In some aspects of the invention, the sample is from the subject’s blood (e.g., whole blood, plasma, or serum) and has a decreased level of one or more cell types set forth in Table 3 and/or Table 8, as compared to a reference level. In some aspects of the invention, the sample is from the subject’s blood (e.g., whole blood, plasma, or serum) and has an increased level of one or more cell types set forth in Table 4 and/or Table 9, as compared to a reference level.

In some aspects of the invention, the method may include the step of measuring or determining a level of 1 or more (e.g., 1 -85), 2 or more (e.g., 2-85), 3 or more (e.g., 3-85), 4 or more (e.g., 4-85), 5 or more (e.g., 5-85), 6 or more (e.g., 6-85), 7 or more (e.g., 7-85), 8 or more (e.g., 8- 85), 9 or more (e.g., 9-85), 10 or more (e.g., 10-85), 1 1 or more (e.g., 1 1 -85), 12 or more (e.g., 12-85), 13 or more (e.g., 13-85), 14 or more (e.g., 14-85), 15 or more (e.g., 15-85), 16 or more (e.g., 16-85),

17 or more (e.g., 17-85), 18 or more (e.g., 18-85), 19 or more (e.g., 19-85), 20 or more (e.g., 20-85),

21 or more (e.g., 21 -85), 22 or more (e.g., 22-85), 23 or more (e.g., 23-85), 24 or more (e.g., 24-85),

25 or more (e.g., 25-85), 26 or more (e.g., 26-85), 27 or more (e.g., 27-85), 28 or more (e.g., 28-85),

29 or more (e.g., 29-85), 30 or more (e.g., 30-85), 31 or more (e.g., 31 -85), 32 or more (e.g., 32-85),

33 or more (e.g., 33-85), 34 or more (e.g., 34-85), 35 or more (e.g., 35-85), 36 or more (e.g., 36-85),

37 or more (e.g., 37-85), 38 or more (e.g., 38-85), 39 or more (e.g., 39-85), 40 or more (e.g., 40-85),

41 or more (e.g., 41 -85), 42 or more (e.g., 42-85), 43 or more (e.g., 43-85), 44 or more (e.g., 44-85),

45 or more (e.g., 45-85), 46 or more (e.g., 46-85), 47 or more (e.g., 47-85), 48 or more (e.g., 48-85),

49 or more (e.g., 49-85), 50 or more (e.g., 50-85), 51 or more (e.g., 51 -85), 52 or more (e.g., 52-85),

53 or more (e.g., 53-85), 54 or more (e.g., 54-85), 55 or more (e.g., 55-85), 56 or more (e.g., 56-85),

57 or more (e.g., 57-85), 58 or more (e.g., 58-85), 59 or more (e.g., 59-85), 60 or more (e.g., 60-85),

61 or more (e.g., 61 -85), 62 or more (e.g., 62-85), 63 or more (e.g., 63-85), 64 or more (e.g., 64-85),

65 or more (e.g., 65-85), 66 or more (e.g., 66-85), 67 or more (e.g., 67-85), 68 or more (e.g., 68-85),

69 or more (e.g., 69-85), 70 or more (e.g., 70-85), 71 or more (e.g., 71 -85), 72 or more (e.g., 72-85),

73 or more (e.g., 73-85), 74 or more (e.g., 74-85), 75 or more (e.g., 75-85), 76 or more (e.g., 76-85),

77 or more (e.g., 77-85), 78 or more (e.g., 78-85), 79 or more (e.g., 79-85), 80 or more (e.g., 80-85),

81 or more (e.g., 81 -85), 82 or more (e.g., 82-85), 83 or more (e.g., 83-85), 84 or more (e.g., 84-85), or 85 of the cell types set forth in Table 3.

In some aspects of the invention, the method may include the step of measuring or determining a level of 1 or more (e.g., 1 -8), 2 or more (e.g., 2-8), 3 or more (e.g., 3-8), 4 or more (e.g., 4-8), 5 or more (e.g., 5-8), 6 or more (e.g., 6-8), 7 or more (e.g., 7-8), or 8 of the cell types set forth in Table 4.

In some aspects of the invention, the method may include the step of measuring or determining 1 or more (e.g., 1 -15), 2 or more (e.g., 2-15), 3 or more (e.g., 3-15), 4 or more (e.g., 4- 15), 5 or more (e.g., 5-15), 6 or more (e.g., 6-15), 7 or more (e.g., 7-15), 8 or more (e.g., 8-15), 9 or more (e.g., 9-15), 10 or more (e.g., 10-15), 1 1 or more (e.g., 1 1 -15), 12 or more (e.g., 12-15), 13 or more (e.g., 13-15), 14 or more (e.g., 14-15), or 15 of the features set forth in Table 5.

In some aspects of the invention, the method may include the step of measuring or determining a level of 1 or more (e.g., 1 -69), 2 or more (e.g., 2-69), 3 or more (e.g., 3-69), 4 or more (e.g., 4-69), 5 or more (e.g., 5-69), 6 or more (e.g., 6-69), 7 or more (e.g., 7-69), 8 or more (e.g., 8- 69), 9 or more (e.g., 9-69), 10 or more (e.g., 10-69), 1 1 or more (e.g., 1 1 -69), 12 or more (e.g., 12-69), 13 or more (e.g., 13-69), 14 or more (e.g., 14-69), 15 or more (e.g., 15-69), 16 or more (e.g., 16-69), 17 or more (e.g., 17-69), 18 or more (e.g., 18-69), 19 or more (e.g., 19-69), 20 or more (e.g., 20-69),

21 or more (e.g., 21 -69), 22 or more (e.g., 22-69), 23 or more (e.g., 23-69), 24 or more (e.g., 24-69),

25 or more (e.g., 25-69), 26 or more (e.g., 26-69), 27 or more (e.g., 27-69), 28 or more (e.g., 28-69),

29 or more (e.g., 29-69), 30 or more (e.g., 30-69), 31 or more (e.g., 31 -69), 32 or more (e.g., 32-69),

33 or more (e.g., 33-69), 34 or more (e.g., 34-69), 35 or more (e.g., 35-69), 36 or more (e.g., 36-69),

37 or more (e.g., 37-69), 38 or more (e.g., 38-69), 39 or more (e.g., 39-69), 40 or more (e.g., 40-69),

41 or more (e.g., 41 -69), 42 or more (e.g., 42-69), 43 or more (e.g., 43-69), 44 or more (e.g., 44-69),

45 or more (e.g., 45-69), 46 or more (e.g., 46-69), 47 or more (e.g., 47-69), 48 or more (e.g., 48-69),

49 or more (e.g., 49-69), 50 or more (e.g., 50-69), 51 or more (e.g., 51 -69), 52 or more (e.g., 52-69),

53 or more (e.g., 53-69), 54 or more (e.g., 54-69), 55 or more (e.g., 55-69), 56 or more (e.g., 56-69),

57 or more (e.g., 57-69), 58 or more (e.g., 58-69), 59 or more (e.g., 59-69), 60 or more (e.g., 60-69),

61 or more (e.g., 61 -69), 62 or more (e.g., 62-69), 63 or more (e.g., 63-69), 64 or more (e.g., 64-69),

65 or more (e.g., 65-69), 66 or more (e.g., 66-69), 67 or more (e.g., 67-69), 68 or more (e.g., 68-69), or 69 of the cell types set forth in Table 6.

In some aspects of the invention, the method may include the step of measuring or determining a level of or 1 or more (e.g., 1 -8), 2 or more (e.g., 2-8), 3 or more (e.g., 3-8), 4 or more (e.g., 4-8), 5 or more (e.g., 5-8), 6 or more (e.g., 6-8), 7 or more (e.g., 7-8), or 8 of the cell types set forth in Table 7.

In some aspects of the invention, the method may include the step of measuring or determining a level of 1 or more (e.g., 1 -80), 2 or more (e.g., 2-80), 3 or more (e.g., 3-80), 4 or more (e.g., 4-80), 5 or more (e.g., 5-80), 6 or more (e.g., 6-80), 7 or more (e.g., 7-80), 8 or more (e.g., 8- 80), 9 or more (e.g., 9-80), 10 or more (e.g., 10-80), 11 or more (e.g., 11 -80), 12 or more (e.g., 12-80), 13 or more (e.g., 13-80), 14 or more (e.g., 14-80), 15 or more (e.g., 15-80), 16 or more (e.g., 16-80),

17 or more (e.g., 17-80), 18 or more (e.g., 18-80), 19 or more (e.g., 19-80), 20 or more (e.g., 20-80),

21 or more (e.g., 21 -80), 22 or more (e.g., 22-80), 23 or more (e.g., 23-80), 24 or more (e.g., 24-80),

25 or more (e.g., 25-80), 26 or more (e.g., 26-80), 27 or more (e.g., 27-80), 28 or more (e.g., 28-80),

29 or more (e.g., 29-80), 30 or more (e.g., 30-80), 31 or more (e.g., 31 -80), 32 or more (e.g., 32-80),

33 or more (e.g., 33-80), 34 or more (e.g., 34-80), 35 or more (e.g., 35-80), 36 or more (e.g., 36-80),

37 or more (e.g., 37-80), 38 or more (e.g., 38-80), 39 or more (e.g., 39-80), 40 or more (e.g., 40-80),

41 or more (e.g., 41 -80), 42 or more (e.g., 42-80), 43 or more (e.g., 43-80), 44 or more (e.g., 44-80),

45 or more (e.g., 45-80), 46 or more (e.g., 46-80), 47 or more (e.g., 47-80), 48 or more (e.g., 48-80),

49 or more (e.g., 49-80), 50 or more (e.g., 50-80), 51 or more (e.g., 51 -80), 52 or more (e.g., 52-80),

53 or more (e.g., 53-80), 54 or more (e.g., 54-80), 55 or more (e.g., 55-80), 56 or more (e.g., 56-80),

57 or more (e.g., 57-80), 58 or more (e.g., 58-80), 59 or more (e.g., 59-80), 60 or more (e.g., 60-80),

61 or more (e.g., 61 -80), 62 or more (e.g., 62-80), 63 or more (e.g., 63-80), 64 or more (e.g., 64-80),

65 or more (e.g., 65-80), 66 or more (e.g., 66-80), 67 or more (e.g., 67-80), 68 or more (e.g., 68-80),

69 or more (e.g., 69-80), 70 or more (e.g., 70-80), 71 or more (e.g., 71 -80), 72 or more (e.g., 72-80),

73 or more (e.g., 73-80), 74 or more (e.g., 74-80), 75 or more (e.g., 75-80), 76 or more (e.g., 76-80), 77 or more (e.g., 77-80), 78 or more (e.g., 78-80), 79 or more (e.g., 79-80), or 80 of the cell types set forth in Table 8.

In some aspects of the invention, the method may include the step of measuring or determining a level of 1 or more (e.g., 1 -8), 2 or more (e.g., 2-8), 3 or more (e.g., 3-8), 4 or more (e.g., 4-8), or 5 of the cell types set forth in Table 9.

In some aspects of the invention, the subject has previously been treated for the MM (e.g., an R/R MM). In some aspects, the subject has received at least one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, or more than fifteen lines of treatment for the MM (e.g., an R/R MM) e.g., is 2L+, 3L+, 4L+, 5L+, 6L+, 7L+, 8L+, 9L+, 10L+, 11 L+, 12L+, 13L+, 14L+, or 15L+. In some aspects, the subject has received at least three prior lines of treatment for the MM (e.g., an R/R MM), e.g., is 4L+, e.g., has received three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, or more than fifteen lines of treatment.

In some aspects, the prior lines of treatment include one or more of a proteasome inhibitor (PI), e.g., bortezomib, carfilzomib, or ixazomib; an immunomodulatory drug (IMiD), e.g., thalidomide, lenalidomide, or pomalidomide; an autologous stem cell transplant (ASCT); an anti-CD38 agent, e.g., daratumumab (DARZALEX®) (U.S. Patent No: 7,829,673 and U.S. Pub. No: 20160067205 A1 ), “MOR202” (U.S. Patent No: 8,263,746), isatuximab (SAR-650984); a CAR-T therapy; a therapy comprising a bispecific antibody; an anti-SLAMF7 therapeutic agent (e.g., an anti-SLAMF7 antibody, e.g., elotuzumab); a nuclear export inhibitor (e.g., selinexor); and a histone deacetylase (HDAC) inhibitor (e.g., panobinostat). In some aspects, the prior lines of treatment include an antibody-drug conjugate (ADC). In some aspects, the prior lines of treatment include a B-cell maturation antigen (BCMA)-directed therapy, e.g., an antibody-drug conjugate targeting BCMA (BCMA-ADC).

In some aspects, the prior lines of treatment include all three of a proteasome inhibitor (PI), an IMiD, and an anti-CD38 agent (e.g., daratumumab).

In some aspects, the MM is refractory to the lines of treatment, e.g., is refractory to one or more of daratumumab, a PI, an IMiD, an ASCT, an anti-CD38 agent, a CAR-T therapy, a therapy comprising a bispecific antibody, an anti-SLAMF7 therapeutic agent, a nuclear export inhibitor, a HDAC inhibitor, an ADC, or a BCMA-directed therapy. In some aspects, the B cell proliferative disorder (e.g., MM) is refractory to daratumumab.

A step of administering a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) may be performed using the dosing regimens described herein.

III. DIAGNOSTIC METHODS

The present invention provides methods useful for diagnosing (e.g., identifying or classifying) subjects having MM who would benefit from treatment with a bispecific antibody that binds to FcRH5 and CD3. The invention is based, in part, on the discovery that (i) certain levels of one or more particular cell types present in a sample (e.g., bone marrow or blood) from a subject and/or (ii) the presence of certain clinical features (e.g., number of prior lines of therapy) about said subject can be used to (i) identify a subject as one who would benefit from treatment with a bispecific antibody that binds to FcRH5 and CD3 and/or (ii) classify a subject into one of three immune profiles: 1 ) an activated immune profile; 2) an inactivated immune profile; or 3) a suppressed immune profile, whereby subjects classified as having an activated immune profile or an inactivated immune profile have been found to benefit from treatment with the bispecific antibody compared to subjects classified as having a suppressed immune profile.

A. Methods of identifying

In some aspects, the invention provides a method of identifying a subject having an MM as one who would benefit from a treatment comprising a bispecific antibody that binds to FcRH5 and CD3. A subject may benefit from the treatment when the subject exhibits a relative increase in overall survival (OS), objective response rate (ORR), progression-free survival (PFS), complete response (CR), partial response (PR), or a combination thereof. The method optionally includes a step of determining a level of one or more cell types set forth in Table 3, Table 4, Table 6, Table 7, Table 8, and/or Table 9 in a sample from the subject and/or determining one or more of the features set forth in Table 5. The sample from the subject may be from the subject’s bone marrow and/or blood.

Flow cytometry (FC), mass spectrometry (MS), immunohistochemistry (IHC), DNA sequencing (DNA-seq), RNA sequencing (RNA-seq), quantitative PCR (qPCR), reverse transcription- quantitative polymerase chain reaction (RT-qPCR), multiplex qPCR or RT-qPCR, microarray analysis, serial analysis of gene expression (SAGE), MASSARRAY® technique, in situ hybridization (ISH), or a combination thereof, may be used to determine the level of one or more cell types in a sample (e.g., bone marrow or blood).

The method of identifying may include a step of identifying the subject as one who would benefit from a treatment comprising a bispecific antibody that binds to FcRH5 and CD3. If the subject has a decreased level of the one or more cell types set forth in Table 3, Table 6, and/or Table 8, as compared to a reference level; an increased level of the one or more cell types set forth in Table 4, Table 7 and/or Table 9, as compared to a reference level; and/or a lower number in one or more of the features set forth in Table 5, as compared to a reference number, then the subject can be identified as one who would benefit from the treatment comprising the bispecific antibody that binds to FcRH5 and CD3. In some aspects, the reference level is a pre-assigned reference level set forth in Table 14. In some aspects, the reference number is a pre-assigned reference number set forth in Table 15.

In some aspects of the invention, if a sample from the subject’s bone marrow has a decreased level of one or more cell types set forth in Table 3 and/or Table 6, as compared to a reference level, then the subject can be identified as one who would benefit from the treatment comprising the bispecific antibody that binds to FcRH5 and CD3. In some aspects of the invention, if a sample from the subject’s bone marrow has an increased level of one or more cell types set forth in Table 4 and/or Table 7, as compared to a reference level, then the subject can be identified as one who would benefit from the treatment comprising the bispecific antibody that binds to FcRH5 and CD3. In some aspects of the invention, if a sample from the subject’s blood (e.g., whole blood, plasma, or serum) has a decreased level of one or more cell types set forth in Table 3 and/or Table 8, as compared to a reference level, then the subject can be identified as one who would benefit from the treatment comprising the bispecific antibody that binds to FcRH5 and CD3. In some aspects of the invention, if a sample from the subject’s blood (e.g., whole blood, plasma, or serum) has an increased level of one or more cell types set forth in Table 4 and/or Table 9, as compared to a reference level, then the subject can be identified as one who would benefit from the treatment comprising the bispecific antibody that binds to FcRH5 and CD3.

An MM subject having an increased level (e.g., presence or percentage) of one or more (e.g., one, two, three, four, five, six, seven, eight, nine, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23,

24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50,

51 , 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 , 72, 73, 74, 75, 76, 77,

78, 79, 80, 81 , 82, 83, 84, or all 85) cell types set forth in Table 3 in a sample (e.g., a baseline sample), as compared to a reference level, may be identified as one who is unlikely to benefit from treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab). For example, a level of a cell type in Table 3 may be increased in a sample from the subject by about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41 %, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 101%, about 102%, about 103%, about 104%, about 105%, about 106%, about 107%, about 108%, about 109%, about 110%, about 111 %, about 112%, about 113%, about 114%, about 115%, about 116%, about 117%, about 118%, about 119%, about 120%, about 121%, about 122%, about 123%, about 124%, about 125%, about 126%, about 127%, about 128%, about 129%, about 130%, about 131%, about 132%, about 133%, about 134%, about 135%, about 136%, about 137%, about 138%, about 139%, about 140%, about 141 %, about 142%, about 143%, about 144%, about 145%, about 146%, about 147%, about 148%, about 149%, about 150%, about 151%, about 152%, about 153%, about 154%, about 155%, about 156%, about 157%, about 158%, about 159%, about 160%, about 161%, about 162%, about 163%, about 164%, about 165%, about 166%, about 167%, about 168%, about 169%, about 170%, about 171%, about 172%, about 173%, about 174%, about 175%, about 176%, about 177%, about 178%, about 179%, about 180%, about 181%, about 182%, about 183%, about 184%, about 185%, about 186%, about 187%, about 188%, about 189%, about 190%, about 191%, about 192%, about 193%, about 194%, about 195%, about 196%, about 197%, about 198%, about 199%, or about 200%, as compared to a reference level, thereby indicating that the subject is unlikely to benefit from treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab).

An MM subject having a decreased level (e.g., presence or percentage) of one or more (e.g., one, two, three, four, five, six, seven, eight, nine, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23,

78, 79, 80, 81 , 82, 83, 84, or all 85) cell types set forth in Table 3 in a sample (e.g., a baseline sample), as compared to a reference level, may be identified as one who is likely to benefit from treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab). For example, a level of a cell type in Table 3 may be decreased in a sample from the subject by about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11 %, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%, as compared to a reference level, thereby indicating that the subject would likely benefit from treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab).

An MM subject having an increased level (e.g., presence or percentage) of one or more (e.g., one, two, three, four, five, six, seven, or all eight) cell types set forth in Table 4 in a sample (e.g., a baseline sample), as compared to a reference level, may be identified as one who is likely to benefit from treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab). For example, a level of a cell type in Table 4 may be increased in a sample from the subject by about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11 %, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41 %, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51 %, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81 %, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91 %, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 101 %, about 102%, about 103%, about 104%, about 105%, about 106%, about 107%, about 108%, about 109%, about 110%, about 111 %, about 112%, about 113%, about 114%, about 115%, about 116%, about 117%, about 118%, about 119%, about 120%, about 121%, about 122%, about 123%, about 124%, about 125%, about 126%, about 127%, about 128%, about 129%, about 130%, about 131%, about 132%, about 133%, about 134%, about 135%, about 136%, about 137%, about 138%, about 139%, about 140%, about 141 %, about 142%, about 143%, about 144%, about 145%, about 146%, about 147%, about 148%, about 149%, about 150%, about 151%, about 152%, about 153%, about 154%, about 155%, about 156%, about 157%, about 158%, about 159%, about 160%, about 161%, about 162%, about 163%, about 164%, about 165%, about 166%, about 167%, about 168%, about 169%, about 170%, about 171%, about 172%, about 173%, about 174%, about 175%, about 176%, about 177%, about 178%, about 179%, about 180%, about 181%, about 182%, about 183%, about 184%, about 185%, about 186%, about 187%, about 188%, about 189%, about 190%, about 191%, about 192%, about 193%, about 194%, about 195%, about 196%, about 197%, about 198%, about 199%, or about 200%, as compared to a reference level, thereby indicating that the subject would likely benefit from treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab).

An MM subject having a decreased level (e.g., presence or percentage) of one or more (e.g., one, two, three, four, five, six, seven, or all eight) cell types set forth in Table 4 in a sample (e.g., a baseline sample), as compared to a reference level, may be identified as one who is unlikely to benefit from treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab). For example, a level of a cell type in Table 4 may be decreased in a sample from the subject by about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41 %, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51 %, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81 %, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91 %, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%, as compared to a reference level, thereby indicating that the subject is unlikely to benefit from treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab).

An MM subject having a higher number in one or more (e.g., one, two, three, four, five, six, seven, eight, nine, 10, 11 , 12, 13, or all 14) features set forth in Table 5, as compared to a reference number, may be identified as one who is unlikely to benefit from treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab). For example, a number in one or more features in Table 5 may be higher by one, two, three, four, five, six, seven, eight, nine, 10, 11 , 12, 13, 14, or 15, as compared to a reference number, thereby indicating that the subject is unlikely to benefit from treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab).

An MM subject having a lower number in one or more (e.g., one, two, three, four, five, six, seven, eight, nine, 10, 11 , 12, 13, or all 14) features set forth in Table 5, as compared to a reference number, may be identified as one who is likely to benefit from treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab). For example, a number in one or more features in Table 5 may be lowered by one, two, three, four, five, six, seven, eight, nine, 10, 11 , 12, 13, 14, or 15, as compared to a reference number, thereby indicating that the subject would likely benefit from treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab).

An MM subject having an increased level (e.g., presence or percentage) of one or more (e.g., one, two, three, four, five, six, seven, eight, nine, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, or all 69) cell types set forth in Table 6 in a bone marrow sample (e.g., a baseline bone marrow sample), as compared to a reference level, may be identified as one who is unlikely to benefit from treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab). For example, in some embodiments, a level of CD4+CD25-CD69+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 27% to about 80% (e.g., about 27% to about 54%, about 40% to about 60%, or about 54% to about 80%), as compared to a reference level. In some embodiments, a level of CD4+DR+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 15% to about 44% (e.g., about 15% to about 29%, about 22% to about 33%, or about 29% to about 44%), as compared to a reference level. In some embodiments, a level of CD4+DR+GzB+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 17% to about 52% (e.g., about 17% to about 34%, about 26% to about 39%, or about 34% to about 52%), as compared to a reference level. In some embodiments, a level of CD4+DR+Ki67+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 28% to about 83% (e.g., about 28% to about 55%, about 42% to about 62%, or about 55% to about 83%), as compared to a reference level. In some embodiments, a level of CD4+DR+PD1 + T cells in a sample (e.g., bone marrow) from the subject is increased by about 26% to about 77% (e.g., about 26% to about 51%, about 38% to about 58%, or about 51% to about 77%), as compared to a reference level. In some embodiments, a level of CD4+Ki67+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 23% to about 68% (e.g., about 23% to about 46%, about 34% to about 51%, or about 46% to about 68%), as compared to a reference level. In some embodiments, a level of CD4+PD1 + T cells in a sample (e.g., bone marrow) from the subject is increased by about 13% to about 40% (e.g., about 13% to about 27%, about 20% to about 30%, or about 27% to about 40%), as compared to a reference level. In some embodiments, a level of CD4+PD1 + T cells in a sample (e.g., bone marrow) from the subject is increased by about 15% to about 45% (e.g., about 15% to about 30%, about 22% to about 34%, or about 30% to about 45%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +GzB+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 18% to about 55% (e.g., about 18% to about 36%, about 27% to about 41 %, or about 36% to about 55%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +Ki67+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 30% to about 89% (e.g., about 30% to about 59%, about 45% to about 67%, or about 59% to about 89%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +OX40- T cells in a sample (e.g., bone marrow) from the subject is increased by about 12% to about 36% (e.g., about 12% to about 24%, about 18% to about 27%, or about 24% to about 36%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +OX40+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 1 1 % to about 34% (e.g., about 1 1 % to about 23%, about 17% to about 26%, or about 23% to about 34%), as compared to a reference level. In some embodiments, a level of CD4+PD1 -TIGIT+TIM3- T cells in a sample (e.g., bone marrow) from the subject is increased by about 9% to about 26% (e.g., about 9% to about 17%, about 13% to about 19%, or about 17% to about 26%), as compared to a reference level. In some embodiments, a level of CD4+TIGIT+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 10% to about 31 % (e.g., about 10% to about 21 %, about 16% to about 23%, or about 21 % to about 31 %), as compared to a reference level. In some embodiments, a level of CD4+DR+ TCM cells in a sample (e.g., bone marrow) from the subject is increased by about 23% to about 70% (e.g., about 23% to about 47%, about 35% to about 53%, or about 47% to about 70%), as compared to a reference level. In some embodiments, a level of CD4+DR+Ki67+ TCM cells in a sample (e.g., bone marrow) from the subject is increased by about 30% to about 91 % (e.g., about 30% to about 61 %, about 46% to about 68%, or about 61 % to about 91 %), as compared to a reference level. In some embodiments, a level of CD4+DR+PD1 + TCM cells in a sample (e.g., bone marrow) from the subject is increased by about 35% to about 104% (e.g., about 35% to about 70%, about 52% to about 78%, or about 70% to about 104%), as compared to a reference level. In some embodiments, a level of CD4+Ki67+ TCM cells in a sample (e.g., bone marrow) from the subject is increased by about 23% to about 68% (e.g., about 23% to about 45%, about 34% to about 51 %, or about 45% to about 68%), as compared to a reference level. In some embodiments, a level of CD4+PD1 + TCM cells in a sample (e.g., bone marrow) from the subject is increased by about 17% to about 51 % (e.g., about 17% to about 34%, about 26% to about 39%, or about 34% to about 51 %), as compared to a reference level. In some embodiments, a level of CD4+PD1 +OX40+ TCM cells in a sample (e.g., bone marrow) from the subject is increased by about 14% to about 42% (e.g., about 14% to about 28%, about 21 % to about 31 %, or about 28% to about 42%), as compared to a reference level. In some embodiments, a level of CD4+DR+ TEM cells in a sample (e.g., bone marrow) from the subject is increased by about 10% to about 31% (e.g., about 10% to about 20%, about 15% to about 23%, or about 20% to about 31%), as compared to a reference level. In some embodiments, a level of CD4+DR+KI67+ TEM cells in a sample (e.g., bone marrow) from the subject is increased by about 20% to about 59% (e.g., about 20% to about 39%, about 30% to about 44%, or about 39% to about 59%), as compared to a reference level. In some embodiments, a level of CD4+DR+PD1 + TEM cells in a sample (e.g., bone marrow) from the subject is increased by about 17% to about 52% (e.g., about 17% to about 35%, about 26% to about 39%, or about 35% to about 52%), as compared to a reference level. In some embodiments, a level of CD4+KI67+ TEM cells in a sample (e.g., bone marrow) from the subject is increased by about 17% to about 52% (e.g., about 17% to about 34%, about 26% to about 39%, or about 34% to about 52%), as compared to a reference level. In some embodiments, a level of CD4+PD1 + TEM cells in a sample (e.g., bone marrow) from the subject is increased by about 9% to about 27% (e.g., about 9% to about 18%, about 14% to about 21%, or about 18% to about 27%), as compared to a reference level. In some embodiments, a level of CD4+ TEM cells in a sample (e.g., bone marrow) from the subject is increased by about 6% to about 19% (e.g., about 6% to about 12%, about 9% to about 14%, or about 12% to about 19%), as compared to a reference level. In some embodiments, a level of CD4+ TEM cells in a sample (e.g., bone marrow) from the subject is increased by about 6% to about 18% (e.g., about 6% to about 12%, about 9% to about 14%, or about 12% to about 18%), as compared to a reference level. In some embodiments, a level of CD4+DR+ TEMRA cells in a sample (e.g., bone marrow) from the subject is increased by about 10% to about 29% (e.g., about 10% to about 20%, about 15% to about 22%, or about 20% to about 29%), as compared to a reference level. In some embodiments, a level of CD4+DR+GzB+ TEMRA cells in a sample (e.g., bone marrow) from the subject is increased by about 11% to about 32% (e.g., about 11% to about 21%, about 16% to about 24%, or about 21% to about 32%), as compared to a reference level. In some embodiments, a level of CD4+DR+KI67+ TEMRA cells in a sample (e.g., bone marrow) from the subject is increased by about 19% to about 56% (e.g., about 19% to about 38%, about 28% to about 42%, or about 38% to about 56%), as compared to a reference level. In some embodiments, a level of CD4+DR+PD1 + TEMRA cells in a sample (e.g., bone marrow) from the subject is increased by about 17% to about 52% (e.g., about 17% to about 34%, about 26% to about 39%, or about 34% to about 52%), as compared to a reference level. In some embodiments, a level of CD4+KI67+ TEMRA cells in a sample (e.g., bone marrow) from the subject is increased by about 17% to about 52% (e.g., about 17% to about 34%, about 26% to about 39%, or about 34% to about 52%), as compared to a reference level. In some embodiments, a level of CD4+PD1 + TEMRA cells in a sample (e.g., bone marrow) from the subject is increased by about 10% to about 29% (e.g., about 10% to about 19%, about 15% to about 22%, or about 19% to about 29%), as compared to a reference level. In some embodiments, a level of CD4+DR+KI67+ TN cells in a sample (e.g., bone marrow) from the subject is increased by about 41% to about 124% (e.g., about 41% to about 83%, about 62% to about 93%, or about 83% to about 124%), as compared to a reference level. In some embodiments, a level of CD4+DR+PD1 + TN cells in a sample (e.g., bone marrow) from the subject is increased by about 38% to about 113% (e.g., about 38% to about 75%, about 56% to about 85%, or about 75% to about 113%), as compared to a reference level. In some embodiments, a level of CD4+KI67+ TN cells in a sample (e.g., bone marrow) from the subject is increased by about 37% to about 110% (e.g., about 37% to about 73%, about 55% to about 82%, or about 73% to about 110%), as compared to a reference level. In some embodiments, a level of CD4+PD1 + TN cells in a sample (e.g., bone marrow) from the subject is increased by about 22% to about 67% (e.g., about 22% to about 45%, about 34% to about 50%, or about 45% to about 67%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +OX40+ TN cells in a sample (e.g., bone marrow) from the subject is increased by about 36% to about 107% (e.g., about 36% to about 71%, about 53% to about 80%, or about 71% to about 107%), as compared to a reference level. In some embodiments, a level of CD8+CD25-CD69+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 10% to about 29% (e.g., about 10% to about 19%, about 14% to about 21 %, or about 19% to about 29%), as compared to a reference level. In some embodiments, a level of CD8+DR+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 6% to about 17% (e.g., about 6% to about 11%, about 9% to about 13%, or about 11 % to about 17%), as compared to a reference level. In some embodiments, a level of CD8+DR+GzB+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 9% to about 26% (e.g., about 9% to about 17%, about 13% to about 19%, or about 17% to about 26%), as compared to a reference level. In some embodiments, a level of CD8+DR+KI67+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 24% to about 72% (e.g., about 24% to about 48%, about 36% to about 54%, or about 48% to about 72%), as compared to a reference level. In some embodiments, a level of CD8+DR+PD1 + T cells in a sample (e.g., bone marrow) from the subject is increased by about 11% to about 34% (e.g., about 11% to about 22%, about 17% to about 25%, or about 22% to about 34%), as compared to a reference level. In some embodiments, a level of CD8+GzB+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 6% to about 19% (e.g., about 6% to about 12%, about 9% to about 14%, or about 12% to about 19%), as compared to a reference level. In some embodiments, a level of CD8+PD1 + T cells in a sample (e.g., bone marrow) from the subject is increased by about 6% to about 19% (e.g., about 6% to about 13%, about 9% to about 14%, or about 13% to about 19%), as compared to a reference level. In some embodiments, a level of CD8+PD1 +GzB+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 9% to about 27% (e.g., about 9% to about 18%, about 13% to about 20%, or about 18% to about 27%), as compared to a reference level. In some embodiments, a level of CD8+PD1 +OX40- T cells in a sample (e.g., bone marrow) from the subject is increased by about 8% to about 23% (e.g., about 8% to about 15%, about 11 % to about 17%, or about 15% to about 23%), as compared to a reference level. In some embodiments, a level of CD8+DR+GzB+ TCM cells in a sample (e.g., bone marrow) from the subject is increased by about 21% to about 62% (e.g., about 21% to about 42%, about 31% to about 47%, or about 42% to about 62%), as compared to a reference level. In some embodiments, a level of CD8+DR+KI67+ TCM cells in a sample (e.g., bone marrow) from the subject is increased by about 26% to about 78% (e.g., about 26% to about 52%, about 39% to about 59%, or about 52% to about 78%), as compared to a reference level. In some embodiments, a level of CD8+DR+PD1 + TCM cells in a sample (e.g., bone marrow) from the subject is increased by about 19% to about 56% (e.g., about 19% to about 37%, about 28% to about 42%, or about 37% to about 56%), as compared to a reference level. In some embodiments, a level of CD8+GzB+ TCM cells in a sample (e.g., bone marrow) from the subject is increased by about 18% to about 54% (e.g., about 18% to about 36%, about 27% to about 41 %, or about 36% to about 54%), as compared to a reference level. In some embodiments, a level of CD8+KI67+ TCM cells in a sample (e.g., bone marrow) from the subject is increased by about 21 % to about 64% (e.g., about 21% to about 42%, about 32% to about 48%, or about 42% to about 64%), as compared to a reference level. In some embodiments, a level of CD8+PD1 + TCM cells in a sample (e.g., bone marrow) from the subject is increased by about 10% to about 31% (e.g., about 10% to about 21 %, about 15% to about 23%, or about 21% to about 31%), as compared to a reference level. In some embodiments, a level of CD8+DR+ TEM cells in a sample (e.g., bone marrow) from the subject is increased by about 7% to about 21% (e.g., about 7% to about 14%, about 11% to about 16%, or about 14% to about 21%), as compared to a reference level. In some embodiments, a level of CD8+DR+GzB+ TEM cells in a sample (e.g., bone marrow) from the subject is increased by about 9% to about 28% (e.g., about 9% to about 19%, about 14% to about 21 %, or about 19% to about 28%), as compared to a reference level. In some embodiments, a level of CD8+DR+KI67+ TEM cells in a sample (e.g., bone marrow) from the subject is increased by about 19% to about 56% (e.g., about 19% to about 37%, about 28% to about 42%, or about 37% to about 56%), as compared to a reference level. In some embodiments, a level of CD8+DR+PD1 + TEM cells in a sample (e.g., bone marrow) from the subject is increased by about 11% to about 33% (e.g., about 11% to about 22%, about 17% to about 25%, or about 22% to about 33%), as compared to a reference level. In some embodiments, a level of CD8+GzB+ TEM cells in a sample (e.g., bone marrow) from the subject is increased by about 7% to about 20% (e.g., about 7% to about 13%, about 10% to about 15%, or about 13% to about 20%), as compared to a reference level. In some embodiments, a level of CD8+PD1 + TEM cells in a sample (e.g., bone marrow) from the subject is increased by about 6% to about 19% (e.g., about 6% to about 13%, about 9% to about 14%, or about 13% to about 19%), as compared to a reference level. In some embodiments, a level of CD8+DR+PD1 + TEMRA cells in a sample (e.g., bone marrow) from the subject is increased by about 8% to about 23% (e.g., about 8% to about 15%, about 11 % to about 17%, or about 15% to about 23%), as compared to a reference level. In some embodiments, a level of CD8+DR+ TN cells in a sample (e.g., bone marrow) from the subject is increased by about 9% to about 27% (e.g., about 9% to about 18%, about 14% to about 20%, or about 18% to about 27%), as compared to a reference level. In some embodiments, a level of CD8+DR+GzB+ TN cells in a sample (e.g., bone marrow) from the subject is increased by about 22% to about 65% (e.g., about 22% to about 43%, about 32% to about 49%, or about 43% to about 65%), as compared to a reference level. In some embodiments, a level of CD8+DR+KI67+ TN cells in a sample (e.g., bone marrow) from the subject is increased by about 30% to about 91% (e.g., about 30% to about 61%, about 46% to about 69%, or about 61% to about 91%), as compared to a reference level. In some embodiments, a level of CD8+DR+PD1 + TN cells in a sample (e.g., bone marrow) from the subject is increased by about 20% to about 59% (e.g., about 20% to about 39%, about 30% to about 44%, or about 39% to about 59%), as compared to a reference level. In some embodiments, a level of CD8+KI67+ TN cells in a sample (e.g., bone marrow) from the subject is increased by about 28% to about 85% (e.g., about 28% to about 57%, about 43% to about 64%, or about 57% to about 85%), as compared to a reference level. In some embodiments, a level of CD8+PD1 + TN cells in a sample (e.g., bone marrow) from the subject is increased by about 10% to about 29% (e.g., about 10% to about 20%, about 15% to about 22%, or about 20% to about 29%), as compared to a reference level. In some embodiments, a level of CD3-DR+ cells in a sample (e.g., bone marrow) from the subject is increased by about 10% to about 30% (e.g., about 10% to about 20%, about 15% to about 22%, or about 20% to about 30%), as compared to a reference level. In some embodiments, a level of 0X40+ Treg cells in a sample (e.g., bone marrow) from the subject is increased by about 13% to about 38% (e.g., about 13% to about 26%, about 19% to about 29%, or about 26% to about 38%), as compared to a reference level. In some embodiments, a level of PD1 +OX40+ Treg cells in a sample (e.g., bone marrow) from the subject is increased by about 16% to about 48% (e.g., about 16% to about 32%, about 24% to about 36%, or about 32% to about 48%), as compared to a reference level. In some embodiments, a level of true NK cells in a sample (e.g., bone marrow) from the subject is increased by about 7% to about 22% (e.g., about 7% to about 15%, about 11 % to about 17%, or about 15% to about 22%), as compared to a reference level.

An MM subject having a decreased level (e.g., presence or percentage) of one or more (e.g., one, two, three, four, five, six, seven, eight, nine, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, or all 69) cell types set forth in Table 6 in a bone marrow sample (e.g., a baseline bone marrow sample), as compared to a reference level, may be identified as one who is likely to benefit from treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab). For example, in some embodiments, a level of CD4+CD25-CD69+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 11 % to about 32% (e.g., about 11 % to about 21 %, about 16% to about 24%, or about 21 % to about 32%), as compared to a reference level. In some embodiments, a level of CD4+DR+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 6% to about 17% (e.g., about 6% to about 12%, about 9% to about 13%, or about 12% to about 17%), as compared to a reference level. In some embodiments, a level of CD4+DR+GzB+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 7% to about 21% (e.g., about 7% to about 14%, about 10% to about 15%, or about 14% to about 21%), as compared to a reference level. In some embodiments, a level of CD4+DR+KI67+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 11 % to about 33% (e.g., about 11 % to about 22%, about 17% to about 25%, or about 22% to about 33%), as compared to a reference level. In some embodiments, a level of CD4+DR+PD1 + T cells in a sample (e.g., bone marrow) from the subject is decreased by about 10% to about 31% (e.g., about 10% to about 20%, about 15% to about 23%, or about 20% to about 31 %), as compared to a reference level. In some embodiments, a level of CD4+KI67+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 9% to about 27% (e.g., about 9% to about 18%, about 14% to about 20%, or about 18% to about 27%), as compared to a reference level. In some embodiments, a level of CD4+PD1 + T cells in a sample (e.g., bone marrow) from the subject is decreased by about 5% to about 16% (e.g., about 5% to about 1 1 %, about 8% to about 12%, or about 1 1 % to about 16%), as compared to a reference level. In some embodiments, a level of CD4+PD1 + T cells in a sample (e.g., bone marrow) from the subject is decreased by about 6% to about 18% (e.g., about 6% to about 12%, about 9% to about 13%, or about 12% to about 18%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +GzB+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 7% to about 22% (e.g., about 7% to about 15%, about 1 1 % to about 16%, or about 15% to about 22%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +KI67+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 12% to about 36% (e.g., about 12% to about 24%, about 18% to about 27%, or about 24% to about 36%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +OX40- T cells in a sample (e.g., bone marrow) from the subject is decreased by about 5% to about 14% (e.g., about 5% to about 10%, about 7% to about 1 1 %, or about 10% to about 14%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +OX40+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 5% to about 14% (e.g., about 5% to about 9%, about 7% to about 10%, or about 9% to about 14%), as compared to a reference level. In some embodiments, a level of CD4+PD1 -TIGIT+TIM3- T cells in a sample (e.g., bone marrow) from the subject is decreased by about 3% to about 10% (e.g., about 3% to about 7%, about 5% to about 8%, or about 7% to about 10%), as compared to a reference level. In some embodiments, a level of CD4+TIGIT+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 4% to about 12% (e.g., about 4% to about 8%, about 6% to about 9%, or about 8% to about 12%), as compared to a reference level. In some embodiments, a level of CD4+DR+ TCM cells in a sample (e.g., bone marrow) from the subject is decreased by about 9% to about 28% (e.g., about 9% to about 19%, about 14% to about 21 %, or about 19% to about 28%), as compared to a reference level. In some embodiments, a level of CD4+DR+KI67+ TCM cells in a sample (e.g., bone marrow) from the subject is decreased by about 12% to about 36% (e.g., about 12% to about 24%, about 18% to about 27%, or about 24% to about 36%), as compared to a reference level. In some embodiments, a level of CD4+DR+PD1 + TCM cells in a sample (e.g., bone marrow) from the subject is decreased by about 14% to about 42% (e.g., about 14% to about 28%, about 21 % to about 31 %, or about 28% to about 42%), as compared to a reference level. In some embodiments, a level of CD4+KI67+ TCM cells in a sample (e.g., bone marrow) from the subject is decreased by about 9% to about 27% (e.g., about 9% to about 18%, about 14% to about 20%, or about 18% to about 27%), as compared to a reference level. In some embodiments, a level of CD4+PD1 + TCM cells in a sample (e.g., bone marrow) from the subject is decreased by about 7% to about 21 % (e.g., about 7% to about 14%, about 10% to about 15%, or about 14% to about 21 %), as compared to a reference level. In some embodiments, a level of CD4+PD1 +OX40+ TCM cells in a sample (e.g., bone marrow) from the subject is decreased by about 6% to about 17% (e.g., about 6% to about 1 1 %, about 8% to about 12%, or about 1 1 % to about 17%), as compared to a reference level. In some embodiments, a level of CD4+DR+ TEM cells in a sample (e.g., bone marrow) from the subject is decreased by about 4% to about 12% (e.g., about 4% to about 8%, about 6% to about 9%, or about 8% to about 12%), as compared to a reference level. In some embodiments, a level of CD4+DR+KI67+ TEM cells in a sample (e.g., bone marrow) from the subject is decreased by about 8% to about 24% (e.g., about 8% to about 16%, about 12% to about 18%, or about 16% to about 24%), as compared to a reference level. In some embodiments, a level of CD4+DR+PD1 + TEM cells in a sample (e.g., bone marrow) from the subject is decreased by about 7% to about 21% (e.g., about 7% to about 14%, about 10% to about 16%, or about 14% to about 21%), as compared to a reference level. In some embodiments, a level of CD4+KI67+ TEM cells in a sample (e.g., bone marrow) from the subject is decreased by about 7% to about 21% (e.g., about 7% to about 14%, about 10% to about 15%, or about 14% to about 21%), as compared to a reference level. In some embodiments, a level of CD4+PD1 + TEM cells in a sample (e.g., bone marrow) from the subject is decreased by about 4% to about 11% (e.g., about 4% to about 7%, about 5% to about 8%, or about 7% to about 11%), as compared to a reference level. In some embodiments, a level of CD4+ TEM cells in a sample (e.g., bone marrow) from the subject is decreased by about 2% to about 7% (e.g., about 2% to about 5%, about 4% to about 6%, or about 5% to about 7%), as compared to a reference level. In some embodiments, a level of CD4+ TEM cells in a sample (e.g., bone marrow) from the subject is decreased by about 2% to about 7% (e.g., about 2% to about 5%, about 4% to about 5%, or about 5% to about 7%), as compared to a reference level. In some embodiments, a level of CD4+DR+ TEMRA cells in a sample (e.g., bone marrow) from the subject is decreased by about 4% to about 12% (e.g., about 4% to about 8%, about 6% to about 9%, or about 8% to about 12%), as compared to a reference level. In some embodiments, a level of CD4+DR+GzB+ TEMRA cells in a sample (e.g., bone marrow) from the subject is decreased by about 4% to about 13% (e.g., about 4% to about 9%, about 6% to about 10%, or about 9% to about 13%), as compared to a reference level. In some embodiments, a level of CD4+DR+KI67+ TEMRA cells in a sample (e.g., bone marrow) from the subject is decreased by about 7% to about 22% (e.g., about 7% to about 15%, about 11% to about 17%, or about 15% to about 22%), as compared to a reference level. In some embodiments, a level of CD4+DR+PD1 + TEMRA cells in a sample (e.g., bone marrow) from the subject is decreased by about 7% to about 21 % (e.g., about 7% to about 14%, about 10% to about 15%, or about 14% to about 21 %), as compared to a reference level. In some embodiments, a level of CD4+KI67+ TEMRA cells in a sample (e.g., bone marrow) from the subject is decreased by about 7% to about 21% (e.g., about 7% to about 14%, about 10% to about 15%, or about 14% to about 21 %), as compared to a reference level. In some embodiments, a level of CD4+PD1 + TEMRA cells in a sample (e.g., bone marrow) from the subject is decreased by about 4% to about 12% (e.g., about 4% to about 8%, about 6% to about 9%, or about 8% to about 12%), as compared to a reference level. In some embodiments, a level of CD4+DR+KI67+ TN cells in a sample (e.g., bone marrow) from the subject is decreased by about 17% to about 50% (e.g., about 17% to about 33%, about 25% to about 37%, or about 33% to about 50%), as compared to a reference level. In some embodiments, a level of CD4+DR+PD1 + TN cells in a sample (e.g., bone marrow) from the subject is decreased by about 15% to about 45% (e.g., about 15% to about 30%, about 22% to about 34%, or about 30% to about 45%), as compared to a reference level. In some embodiments, a level of CD4+KI67+ TN cells in a sample (e.g., bone marrow) from the subject is decreased by about 15% to about 44% (e.g., about 15% to about 29%, about 22% to about 33%, or about 29% to about 44%), as compared to a reference level. In some embodiments, a level of CD4+PD1 + TN cells in a sample (e.g., bone marrow) from the subject is decreased by about 9% to about 27% (e.g., about 9% to about 18%, about 13% to about 20%, or about 18% to about 27%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +0X40+ TN cells in a sample (e.g., bone marrow) from the subject is decreased by about 14% to about 42% (e.g., about 14% to about 28%, about 21% to about 32%, or about 28% to about 42%), as compared to a reference level. In some embodiments, a level of CD8+CD25-CD69+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 4% to about 11% (e.g., about 4% to about 8%, about 6% to about 9%, or about 8% to about 11%), as compared to a reference level. In some embodiments, a level of CD8+DR+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 2% to about 7% (e.g., about 2% to about 5%, about 3% to about 5%, or about 5% to about 7%), as compared to a reference level. In some embodiments, a level of CD8+DR+GzB+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 3% to about 10% (e.g., about 3% to about 7%, about 5% to about 8%, or about 7% to about 10%), as compared to a reference level. In some embodiments, a level of CD8+DR+KI67+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 10% to about 29% (e.g., about 10% to about 19%, about 14% to about 22%, or about 19% to about 29%), as compared to a reference level. In some embodiments, a level of CD8+DR+PD1 + T cells in a sample (e.g., bone marrow) from the subject is decreased by about 4% to about 13% (e.g., about 4% to about 9%, about 7% to about 10%, or about 9% to about 13%), as compared to a reference level. In some embodiments, a level of CD8+GzB+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 2% to about 7% (e.g., about 2% to about 5%, about 4% to about 6%, or about 5% to about 7%), as compared to a reference level. In some embodiments, a level of CD8+PD1 + T cells in a sample (e.g., bone marrow) from the subject is decreased by about 3% to about 8% (e.g., about 3% to about 5%, about 4% to about 6%, or about 5% to about 8%), as compared to a reference level. In some embodiments, a level of CD8+PD1 +GzB+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 4% to about 11% (e.g., about 4% to about 7%, about 5% to about 8%, or about 7% to about 11%), as compared to a reference level. In some embodiments, a level of CD8+PD1 +OX40- T cells in a sample (e.g., bone marrow) from the subject is decreased by about 3% to about 9% (e.g., about 3% to about 6%, about 5% to about 7%, or about 6% to about 9%), as compared to a reference level. In some embodiments, a level of CD8+DR+GzB+ TCM cells in a sample (e.g., bone marrow) from the subject is decreased by about 8% to about 25% (e.g., about 8% to about 17%, about 12% to about 19%, or about 17% to about 25%), as compared to a reference level. In some embodiments, a level of CD8+DR+KI67+ TCM cells in a sample (e.g., bone marrow) from the subject is decreased by about 10% to about 31% (e.g., about 10% to about 21%, about 16% to about 23%, or about 21% to about 31%), as compared to a reference level. In some embodiments, a level of CD8+DR+PD1 + TCM cells in a sample (e.g., bone marrow) from the subject is decreased by about 7% to about 22% (e.g., about 7% to about 15%, about 1 1 % to about 17%, or about 15% to about 22%), as compared to a reference level. In some embodiments, a level of CD8+GzB+ TCM cells in a sample (e.g., bone marrow) from the subject is decreased by about 7% to about 22% (e.g., about 7% to about 14%, about 1 1 % to about 16%, or about 14% to about 22%), as compared to a reference level. In some embodiments, a level of CD8+KI67+ TCM cells in a sample (e.g., bone marrow) from the subject is decreased by about 8% to about 25% (e.g., about 8% to about 17%, about 13% to about 19%, or about 17% to about 25%), as compared to a reference level. In some embodiments, a level of CD8+PD1 + TCM cells in a sample (e.g., bone marrow) from the subject is decreased by about 4% to about 12% (e.g., about 4% to about 8%, about 6% to about 9%, or about 8% to about 12%), as compared to a reference level. In some embodiments, a level of CD8+DR+ TEM cells in a sample (e.g., bone marrow) from the subject is decreased by about 3% to about 9% (e.g., about 3% to about 6%, about 4% to about 6%, or about 6% to about 9%), as compared to a reference level. In some embodiments, a level of CD8+DR+GzB+ TEM cells in a sample (e.g., bone marrow) from the subject is decreased by about 4% to about 1 1 % (e.g., about 4% to about 8%, about 6% to about 8%, or about 8% to about 1 1 %), as compared to a reference level. In some embodiments, a level of CD8+DR+KI67+ TEM cells in a sample (e.g., bone marrow) from the subject is decreased by about 7% to about 22% (e.g., about 7% to about 15%, about 1 1 % to about 17%, or about 15% to about 22%), as compared to a reference level. In some embodiments, a level of CD8+DR+PD1 + TEM cells in a sample (e.g., bone marrow) from the subject is decreased by about 4% to about 13% (e.g., about 4% to about 9%, about 7% to about 10%, or about 9% to about 13%), as compared to a reference level. In some embodiments, a level of CD8+GzB+ TEM cells in a sample (e.g., bone marrow) from the subject is decreased by about 3% to about 8% (e.g., about 3% to about 5%, about 4% to about 6%, or about 5% to about 8%), as compared to a reference level. In some embodiments, a level of CD8+PD1 + TEM cells in a sample (e.g., bone marrow) from the subject is decreased by about 2% to about 7% (e.g., about 2% to about 5%, about 4% to about 6%, or about 5% to about 7%), as compared to a reference level. In some embodiments, a level of CD8+DR+PD1 + TEMRA cells in a sample (e.g., bone marrow) from the subject is decreased by about 3% to about 9% (e.g., about 3% to about 6%, about 5% to about 7%, or about 6% to about 9%), as compared to a reference level. In some embodiments, a level of CD8+DR+ TN cells in a sample (e.g., bone marrow) from the subject is decreased by about 4% to about 1 1 % (e.g., about 4% to about 7%, about 5% to about 8%, or about 7% to about 1 1 %), as compared to a reference level. In some embodiments, a level of CD8+DR+GzB+ TN cells in a sample (e.g., bone marrow) from the subject is decreased by about 9% to about 26% (e.g., about 9% to about 17%, about 13% to about 19%, or about 17% to about 26%), as compared to a reference level. In some embodiments, a level of CD8+DR+KI67+ TN cells in a sample (e.g., bone marrow) from the subject is decreased by about 12% to about 36% (e.g., about 12% to about 24%, about 18% to about 27%, or about 24% to about 36%), as compared to a reference level. In some embodiments, a level of CD8+DR+PD1 + TN cells in a sample (e.g., bone marrow) from the subject is decreased by about 8% to about 24% (e.g., about 8% to about 16%, about 12% to about 18%, or about 16% to about 24%), as compared to a reference level. In some embodiments, a level of CD8+KI67+ TN cells in a sample (e.g., bone marrow) from the subject is decreased by about 1 1 % to about 34% (e.g., about 1 1 % to about 23%, about 17% to about 25%, or about 23% to about 34%), as compared to a reference level. In some embodiments, a level of CD8+PD1 + TN cells in a sample (e.g., bone marrow) from the subject is decreased by about 4% to about 12% (e.g., about 4% to about 8%, about 6% to about 9%, or about 8% to about 12%), as compared to a reference level. In some embodiments, a level of CD3-DR+ cells in a sample (e.g., bone marrow) from the subject is decreased by about 4% to about 12% (e.g., about 4% to about 8%, about 6% to about 9%, or about 8% to about 12%), as compared to a reference level. In some embodiments, a level of 0X40+ Treg cells in a sample (e.g., bone marrow) from the subject is decreased by about 5% to about 15% (e.g., about 5% to about 10%, about 8% to about 1 1 %, or about 10% to about 15%), as compared to a reference level. In some embodiments, a level of PD1 +OX40+ Treg cells in a sample (e.g., bone marrow) from the subject is decreased by about 6% to about 19% (e.g., about 6% to about 13%, about 9% to about 14%, or about 13% to about 19%), as compared to a reference level. In some embodiments, a level of true NK cells in a sample (e.g., bone marrow) from the subject is decreased by about 3% to about 9% (e.g., about 3% to about 6%, about 4% to about 7%, or about 6% to about 9%), as compared to a reference level.

An MM subject having an increased level (e.g., presence or percentage) of one or more (e.g., one, two, three, four, five, six, seven, or all eight) cell types set forth in Table 7 in a bone marrow sample (e.g., a baseline bone marrow sample), as compared to a reference level, may be identified as one who is likely to benefit from treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab). For example, in some embodiments, a level of CD4+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 4% to about 12% (e.g., about 4% to about 8%, about 6% to about 9%, or about 8% to about 12%), as compared to a reference level. In some embodiments, a level of CD4+CD25+CD69- T cells in a sample (e.g., bone marrow) from the subject is increased by about 3% to about 10% (e.g., about 3% to about 7%, about 5% to about 7%, or about 7% to about 10%), as compared to a reference level. In some embodiments, a level of CD4+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 3% to about 10% (e.g., about 3% to about 7%, about 5% to about 8%, or about 7% to about 10%), as compared to a reference level. In some embodiments, a level of CD4+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 5% to about 14% (e.g., about 5% to about 9%, about 7% to about 1 1 %, or about 9% to about 14%), as compared to a reference level. In some embodiments, a level of CD4+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 4% to about 12% (e.g., about 4% to about 8%, about 6% to about 9%, or about 8% to about 12%), as compared to a reference level. In some embodiments, a level of CD4+ TCM cells in a sample (e.g., bone marrow) from the subject is increased by about 4% to about 1 1 % (e.g., about 4% to about 7%, about 5% to about 8%, or about 7% to about 1 1 %), as compared to a reference level. In some embodiments, a level of CD4+ TCM cells in a sample (e.g., bone marrow) from the subject is increased by about 4% to about 1 1 % (e.g., about 4% to about 7%, about 5% to about 8%, or about 7% to about 1 1 %), as compared to a reference level. In some embodiments, a level of CD8+CD25+CD69- T cells in a sample (e.g., bone marrow) from the subject is increased by about 11% to about 33% (e.g., about 11 % to about 22%, about 17% to about 25%, or about 22% to about 33%), as compared to a reference level. In some embodiments, a level of CD8+NK T cells in a sample (e.g., bone marrow) from the subject is increased by about 3% to about 9% (e.g., about 3% to about 6%, about 5% to about 7%, or about 6% to about 9%), as compared to a reference level. In some embodiments, a level of CD8+ TCM cells in a sample (e.g., bone marrow) from the subject is increased by about 8% to about 25% (e.g., about 8% to about 16%, about 12% to about 18%, or about 16% to about 25%), as compared to a reference level. In some embodiments, a level of CD8+ TCM cells in a sample (e.g., bone marrow) from the subject is increased by about 9% to about 26% (e.g., about 9% to about 17%, about 13% to about 19%, or about 17% to about 26%), as compared to a reference level. In some embodiments, a level of CD8+ TN cells in a sample (e.g., bone marrow) from the subject is increased by about 6% to about 19% (e.g., about 6% to about 12%, about 9% to about 14%, or about 12% to about 19%), as compared to a reference level. In some embodiments, a level of CD8+ TN cells in a sample (e.g., bone marrow) from the subject is increased by about 8% to about 23% (e.g., about 8% to about 15%, about 11 % to about 17%, or about 15% to about 23%), as compared to a reference level. In some embodiments, a level of CD25+CD69- NK cells in a sample (e.g., bone marrow) from the subject is increased by about 5% to about 15% (e.g., about 5% to about 10%, about 8% to about 11 %, or about 10% to about 15%), as compared to a reference level.

An MM subject having a decreased level (e.g., presence or percentage) of one or more (e.g., one, two, three, four, five, six, seven, or all eight) cell types set forth in Table 7 in a bone marrow sample (e.g., a baseline bone marrow sample), as compared to a reference level, may be identified as one who is unlikely to benefit from treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab). For example, in some embodiments, a level of CD4+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 10% to about 29% (e.g., about 10% to about 19%, about 15% to about 22%, or about 19% to about 29%), as compared to a reference level. In some embodiments, a level of CD4+CD25+CD69- T cells in a sample (e.g., bone marrow) from the subject is decreased by about 8% to about 25% (e.g., about 8% to about 16%, about 12% to about 18%, or about 16% to about 25%), as compared to a reference level. In some embodiments, a level of CD4+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 9% to about 26% (e.g., about 9% to about 17%, about 13% to about 19%, or about 17% to about 26%), as compared to a reference level. In some embodiments, a level of CD4+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 12% to about 36% (e.g., about 12% to about 24%, about 18% to about 27%, or about 24% to about 36%), as compared to a reference level. In some embodiments, a level of CD4+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 10% to about 31 % (e.g., about 10% to about 21 %, about 16% to about 23%, or about 21 % to about 31%), as compared to a reference level. In some embodiments, a level of CD4+ TCM cells in a sample (e.g., bone marrow) from the subject is decreased by about 9% to about 27% (e.g., about 9% to about 18%, about 14% to about 20%, or about 18% to about 27%), as compared to a reference level. In some embodiments, a level of CD4+ TCM cells in a sample (e.g., bone marrow) from the subject is decreased by about 9% to about 27% (e.g., about 9% to about 18%, about 14% to about 20%, or about 18% to about 27%), as compared to a reference level. In some embodiments, a level of CD8+CD25+CD69- T cells in a sample (e.g., bone marrow) from the subject is decreased by about 28% to about 83% (e.g., about 28% to about 55%, about 41% to about 62%, or about 55% to about 83%), as compared to a reference level. In some embodiments, a level of CD8+NK T cells in a sample (e.g., bone marrow) from the subject is decreased by about 8% to about 23% (e.g., about 8% to about 16%, about 12% to about 17%, or about 16% to about 23%), as compared to a reference level. In some embodiments, a level of CD8+ TCM cells in a sample (e.g., bone marrow) from the subject is decreased by about 20% to about 61% (e.g., about 20% to about 41%, about 31 % to about 46%, or about 41% to about 61%), as compared to a reference level. In some embodiments, a level of CD8+ TCM cells in a sample (e.g., bone marrow) from the subject is decreased by about 21% to about 64% (e.g., about 21% to about 43%, about 32% to about 48%, or about 43% to about 64%), as compared to a reference level. In some embodiments, a level of CD8+ TN cells in a sample (e.g., bone marrow) from the subject is decreased by about 16% to about 47% (e.g., about 16% to about 31%, about 23% to about 35%, or about 31% to about 47%), as compared to a reference level. In some embodiments, a level of CD8+ TN cells in a sample (e.g., bone marrow) from the subject is decreased by about 19% to about 57% (e.g., about 19% to about 38%, about 29% to about 43%, or about 38% to about 57%), as compared to a reference level. In some embodiments, a level of CD25+CD69- NK cells in a sample (e.g., bone marrow) from the subject is decreased by about 13% to about 38% (e.g., about 13% to about 25%, about 19% to about 29%, or about 25% to about 38%), as compared to a reference level.

An MM subject having an increased level (e.g., presence or percentage) of one or more (e.g., one, two, three, four, five, six, seven, eight, nine, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, or all 80) cell types set forth in Table 8 in a blood sample (e.g., a baseline blood sample), as compared to a reference level, may be identified as one who is unlikely to benefit from treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab). For example, in some embodiments, a level of CD8+DR+ TCM cells in a sample (e.g., bone marrow) from the subject is increased by about 14% to about 43% (e.g., about 14% to about 29%, about 22% to about 32%, or about 29% to about 43%), as compared to a reference level. In some embodiments, a level of CD4+DR+ T cells in a sample (e.g., blood) from the subject is increased by about 19% to about 57% (e.g., about 19% to about 38%, about 28% to about 42%, or about 38% to about 57%), as compared to a reference level. In some embodiments, a level of CD4+DR+GzB+ T cells in a sample (e.g., blood) from the subject is increased by about 17% to about 51 % (e.g., about 17% to about 34%, about 26% to about 38%, or about 34% to about 51%), as compared to a reference level. In some embodiments, a level of CD4+DR+KI67+ T cells in a sample (e.g., blood) from the subject is increased by about 24% to about 73% (e.g., about 24% to about 49%, about 37% to about 55%, or about 49% to about 73%), as compared to a reference level. In some embodiments, a level of CD4+DR+PD1 + T cells in a sample (e.g., blood) from the subject is increased by about 26% to about 79% (e.g., about 26% to about 53%, about 39% to about 59%, or about 53% to about 79%), as compared to a reference level. In some embodiments, a level of CD4+KI67+ T cells in a sample (e.g., blood) from the subject is increased by about 22% to about 65% (e.g., about 22% to about 43%, about 32% to about 48%, or about 43% to about 65%), as compared to a reference level. In some embodiments, a level of CD4+PD1 + T cells in a sample (e.g., blood) from the subject is increased by about 13% to about 38% (e.g., about 13% to about 26%, about 19% to about 29%, or about 26% to about 38%), as compared to a reference level. In some embodiments, a level of CD4+PD1 + T cells in a sample (e.g., blood) from the subject is increased by about 14% to about 41% (e.g., about 14% to about 27%, about 21% to about 31%, or about 27% to about 41%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +KI67+ T cells in a sample (e.g., blood) from the subject is increased by about 26% to about 77% (e.g., about 26% to about 52%, about 39% to about 58%, or about 52% to about 77%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +OX40- T cells in a sample (e.g., blood) from the subject is increased by about 5% to about 15% (e.g., about 5% to about 10%, about 7% to about 11 %, or about 10% to about 15%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +0X40+ T cells in a sample (e.g., blood) from the subject is increased by about 11% to about 34% (e.g., about 11% to about 23%, about 17% to about 26%, or about 23% to about 34%), as compared to a reference level. In some embodiments, a level of CD4+PD1 -TIGIT+TIM3- T cells in a sample (e.g., blood) from the subject is increased by about 12% to about 35% (e.g., about 12% to about 23%, about 17% to about 26%, or about 23% to about 35%), as compared to a reference level. In some embodiments, a level of CD4+PDL1 + T cells in a sample (e.g., blood) from the subject is increased by about 15% to about 45% (e.g., about 15% to about 30%, about 23% to about 34%, or about 30% to about 45%), as compared to a reference level. In some embodiments, a level of CD4+TIGIT+ T cells in a sample (e.g., blood) from the subject is increased by about 11 % to about 34% (e.g., about 11 % to about 23%, about 17% to about 26%, or about 23% to about 34%), as compared to a reference level. In some embodiments, a level of CD4+DR+ TCM cells in a sample (e.g., blood) from the subject is increased by about 26% to about 77% (e.g., about 26% to about 52%, about 39% to about 58%, or about 52% to about 77%), as compared to a reference level. In some embodiments, a level of CD4+DR+KI67+ TCM cells in a sample (e.g., blood) from the subject is increased by about 25% to about 74% (e.g., about 25% to about 49%, about 37% to about 55%, or about 49% to about 74%), as compared to a reference level. In some embodiments, a level of CD4+DR+PD1 + TCM cells in a sample (e.g., blood) from the subject is increased by about 34% to about 102% (e.g., about 34% to about 68%, about 51 % to about 76%, or about 68% to about 102%), as compared to a reference level. In some embodiments, a level of CD4+KI67+ TCM cells in a sample (e.g., blood) from the subject is increased by about 19% to about 57% (e.g., about 19% to about 38%, about 28% to about 43%, or about 38% to about 57%), as compared to a reference level. In some embodiments, a level of CD4+PD1 + TCM cells in a sample (e.g., blood) from the subject is increased by about 15% to about 46% (e.g., about 15% to about 31 %, about 23% to about 35%, or about 31 % to about 46%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +OX40+ TCM cells in a sample (e.g., blood) from the subject is increased by about 12% to about 37% (e.g., about 12% to about 25%, about 18% to about 28%, or about 25% to about 37%), as compared to a reference level. In some embodiments, a level of CD4+DR+ TEM cells in a sample (e.g., blood) from the subject is increased by about 13% to about 38% (e.g., about 13% to about 26%, about 19% to about 29%, or about 26% to about 38%), as compared to a reference level. In some embodiments, a level of CD4+DR+KI67+ TEM cells in a sample (e.g., blood) from the subject is increased by about 19% to about 57% (e.g., about 19% to about 38%, about 28% to about 43%, or about 38% to about 57%), as compared to a reference level. In some embodiments, a level of CD4+DR+PD1 + TEM cells in a sample (e.g., blood) from the subject is increased by about 18% to about 53% (e.g., about 18% to about 35%, about 27% to about 40%, or about 35% to about 53%), as compared to a reference level. In some embodiments, a level of CD4+KI67+ TEM cells in a sample (e.g., blood) from the subject is increased by about 18% to about 53% (e.g., about 18% to about 35%, about 27% to about 40%, or about 35% to about 53%), as compared to a reference level. In some embodiments, a level of CD4+PD1 + TEM cells in a sample (e.g., blood) from the subject is increased by about 8% to about 24% (e.g., about 8% to about 16%, about 12% to about 18%, or about 16% to about 24%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +OX40+ TEM cells in a sample (e.g., blood) from the subject is increased by about 8% to about 23% (e.g., about 8% to about 15%, about 1 1 % to about 17%, or about 15% to about 23%), as compared to a reference level. In some embodiments, a level of CD4+DR+ TEMRA cells in a sample (e.g., blood) from the subject is increased by about 15% to about 46% (e.g., about 15% to about 31 %, about 23% to about 35%, or about 31 % to about 46%), as compared to a reference level. In some embodiments, a level of CD4+DR+GzB+ TEMRA cells in a sample (e.g., blood) from the subject is increased by about 14% to about 41 % (e.g., about 14% to about 27%, about 20% to about 31 %, or about 27% to about 41 %), as compared to a reference level. In some embodiments, a level of CD4+DR+KI67+ TEMRA cells in a sample (e.g., blood) from the subject is increased by about 23% to about 68% (e.g., about 23% to about 46%, about 34% to about 51 %, or about 46% to about 68%), as compared to a reference level. In some embodiments, a level of CD4+DR+PD1 + TEMRA cells in a sample (e.g., blood) from the subject is increased by about 21 % to about 63% (e.g., about 21 % to about 42%, about 31 % to about 47%, or about 42% to about 63%), as compared to a reference level. In some embodiments, a level of CD4+KI67+ TEMRA cells in a sample (e.g., blood) from the subject is increased by about 21 % to about 63% (e.g., about 21 % to about 42%, about 32% to about 47%, or about 42% to about 63%), as compared to a reference level. In some embodiments, a level of CD4+PD1 + TEMRA cells in a sample (e.g., blood) from the subject is increased by about 9% to about 28% (e.g., about 9% to about 19%, about 14% to about 21 %, or about 19% to about 28%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +0X40+ TEMRA cells in a sample (e.g., blood) from the subject is increased by about 10% to about 29% (e.g., about 10% to about 20%, about 15% to about 22%, or about 20% to about 29%), as compared to a reference level. In some embodiments, a level of CD4+DR+ TN cells in a sample (e.g., blood) from the subject is increased by about 19% to about 58% (e.g., about 19% to about 39%, about 29% to about 44%, or about 39% to about 58%), as compared to a reference level. In some embodiments, a level of CD4+DR+KI67+ TN cells in a sample (e.g., blood) from the subject is increased by about 38% to about 1 14% (e.g., about 38% to about 76%, about 57% to about 85%, or about 76% to about 1 14%), as compared to a reference level. In some embodiments, a level of CD4+DR+PD1 + TN cells in a sample (e.g., blood) from the subject is increased by about 53% to about 160% (e.g., about 53% to about 107%, about 80% to about 120%, or about 107% to about 160%), as compared to a reference level. In some embodiments, a level of CD4+KI67+ TN cells in a sample (e.g., blood) from the subject is increased by about 27% to about 81 % (e.g., about 27% to about 54%, about 41 % to about 61 %, or about 54% to about 81 %), as compared to a reference level. In some embodiments, a level of CD4+PD1 + TN cells in a sample (e.g., blood) from the subject is increased by about 19% to about 58% (e.g., about 19% to about 39%, about 29% to about 44%, or about 39% to about 58%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +0X40+ TN cells in a sample (e.g., blood) from the subject is increased by about 18% to about 54% (e.g., about 18% to about 36%, about 27% to about 41 %, or about 36% to about 54%), as compared to a reference level. In some embodiments, a level of CD8+DR+ T cells in a sample (e.g., blood) from the subject is increased by about 8% to about 25% (e.g., about 8% to about 17%, about 13% to about 19%, or about 17% to about 25%), as compared to a reference level. In some embodiments, a level of CD8+DR+GzB+ T cells in a sample (e.g., blood) from the subject is increased by about 9% to about 28% (e.g., about 9% to about 18%, about 14% to about 21 %, or about 18% to about 28%), as compared to a reference level. In some embodiments, a level of CD8+DR+KI67+ T cells in a sample (e.g., blood) from the subject is increased by about 25% to about 74% (e.g., about 25% to about 49%, about 37% to about 56%, or about 49% to about 74%), as compared to a reference level. In some embodiments, a level of CD8+DR+PD1 + T cells in a sample (e.g., blood) from the subject is increased by about 15% to about 44% (e.g., about 15% to about 29%, about 22% to about 33%, or about 29% to about 44%), as compared to a reference level. In some embodiments, a level of CD8+GzB+ T cells in a sample (e.g., blood) from the subject is increased by about 6% to about 18% (e.g., about 6% to about 12%, about 9% to about 14%, or about 12% to about 18%), as compared to a reference level. In some embodiments, a level of CD8+KI67+ T cells in a sample (e.g., blood) from the subject is increased by about 22% to about 67% (e.g., about 22% to about 45%, about 34% to about 50%, or about 45% to about 67%), as compared to a reference level. In some embodiments, a level of CD8+PD1 + T cells in a sample (e.g., blood) from the subject is increased by about 9% to about 26% (e.g., about 9% to about 18%, about 13% to about 20%, or about 18% to about 26%), as compared to a reference level. In some embodiments, a level of CD8+PD1 + T cells in a sample (e.g., blood) from the subject is increased by about 8% to about 24% (e.g., about 8% to about 16%, about 12% to about 18%, or about 16% to about 24%), as compared to a reference level. In some embodiments, a level of CD8+PD1 +GzB+ T cells in a sample (e.g., blood) from the subject is increased by about 1 1 % to about 34% (e.g., about 1 1 % to about 23%, about 17% to about 26%, or about 23% to about 34%), as compared to a reference level. In some embodiments, a level of CD8+PD1 +KI67+ T cells in a sample (e.g., blood) from the subject is increased by about 26% to about 78% (e.g., about 26% to about 52%, about 39% to about 59%, or about 52% to about 78%), as compared to a reference level. In some embodiments, a level of CD8+DR+ TCM cells in a sample (e.g., blood) from the subject is increased by about 14% to about 43% (e.g., about 14% to about 28%, about 21% to about 32%, or about 28% to about 43%), as compared to a reference level. In some embodiments, a level of CD8+DR+GzB+ TCM cells in a sample (e.g., blood) from the subject is increased by about 20% to about 61% (e.g., about 20% to about 41%, about 31% to about 46%, or about 41 % to about 61%), as compared to a reference level. In some embodiments, a level of CD8+DR+KI67+ TCM cells in a sample (e.g., blood) from the subject is increased by about 18% to about 54% (e.g., about 18% to about 36%, about 27% to about 40%, or about 36% to about 54%), as compared to a reference level. In some embodiments, a level of CD8+DR+PD1 + TCM cells in a sample (e.g., blood) from the subject is increased by about 17% to about 51% (e.g., about 17% to about 34%, about 25% to about 38%, or about 34% to about 51%), as compared to a reference level. In some embodiments, a level of CD8+GzB+ TCM cells in a sample (e.g., blood) from the subject is increased by about 18% to about 55% (e.g., about 18% to about 37%, about 27% to about 41 %, or about 37% to about 55%), as compared to a reference level. In some embodiments, a level of CD8+KI67+ TCM cells in a sample (e.g., blood) from the subject is increased by about 16% to about 49% (e.g., about 16% to about 33%, about 25% to about 37%, or about 33% to about 49%), as compared to a reference level. In some embodiments, a level of CD8+PD1 + TCM cells in a sample (e.g., blood) from the subject is increased by about 11% to about 34% (e.g., about 11% to about 23%, about 17% to about 25%, or about 23% to about 34%), as compared to a reference level. In some embodiments, a level of CD8+PD1 +0X40+ TCM cells in a sample (e.g., blood) from the subject is increased by about 14% to about 43% (e.g., about 14% to about 28%, about 21 % to about 32%, or about 28% to about 43%), as compared to a reference level. In some embodiments, a level of CD8+DR+ TEM cells in a sample (e.g., blood) from the subject is increased by about 7% to about 22% (e.g., about 7% to about 15%, about 11 % to about 17%, or about 15% to about 22%), as compared to a reference level. In some embodiments, a level of CD8+DR+GzB+ TEM cells in a sample (e.g., blood) from the subject is increased by about 8% to about 24% (e.g., about 8% to about 16%, about 12% to about 18%, or about 16% to about 24%), as compared to a reference level. In some embodiments, a level of CD8+DR+KI67+ TEM cells in a sample (e.g., blood) from the subject is increased by about 18% to about 55% (e.g., about 18% to about 36%, about 27% to about 41 %, or about 36% to about 55%), as compared to a reference level. In some embodiments, a level of CD8+DR+PD1 + TEM cells in a sample (e.g., blood) from the subject is increased by about 11% to about 34% (e.g., about 11 % to about 23%, about 17% to about 26%, or about 23% to about 34%), as compared to a reference level. In some embodiments, a level of CD8+GzB+ TEM cells in a sample (e.g., blood) from the subject is increased by about 6% to about 17% (e.g., about 6% to about 11%, about 8% to about 13%, or about 11 % to about 17%), as compared to a reference level. In some embodiments, a level of CD8+KI67+ TEM cells in a sample (e.g., blood) from the subject is increased by about 16% to about 47% (e.g., about 16% to about 31 %, about 23% to about 35%, or about 31 % to about 47%), as compared to a reference level. In some embodiments, a level of CD8+PD1 + TEM cells in a sample (e.g., blood) from the subject is increased by about 6% to about 18% (e.g., about 6% to about 12%, about 9% to about 14%, or about 12% to about 18%), as compared to a reference level. In some embodiments, a level of CD8+DR+ TEMRA cells in a sample (e.g., blood) from the subject is increased by about 5% to about 16% (e.g., about 5% to about 11%, about 8% to about 12%, or about 11% to about 16%), as compared to a reference level. In some embodiments, a level of CD8+DR+KI67+ TEMRA cells in a sample (e.g., blood) from the subject is increased by about 23% to about 69% (e.g., about 23% to about 46%, about 34% to about 52%, or about 46% to about 69%), as compared to a reference level. In some embodiments, a level of CD8+DR+PD1 + TEMRA cells in a sample (e.g., blood) from the subject is increased by about 11% to about 34% (e.g., about 11% to about 23%, about 17% to about 26%, or about 23% to about 34%), as compared to a reference level. In some embodiments, a level of CD8+GzB+ TEMRA cells in a sample (e.g., blood) from the subject is increased by about 3% to about 8% (e.g., about 3% to about 5%, about 4% to about 6%, or about 5% to about 8%), as compared to a reference level. In some embodiments, a level of CD8+KI67+ TEMRA cells in a sample (e.g., blood) from the subject is increased by about 22% to about 65% (e.g., about 22% to about 43%, about 32% to about 48%, or about 43% to about 65%), as compared to a reference level. In some embodiments, a level of CD8+PD1 + TEMRA cells in a sample (e.g., blood) from the subject is increased by about 7% to about 21 % (e.g., about 7% to about 14%, about 11% to about 16%, or about 14% to about 21%), as compared to a reference level. In some embodiments, a level of CD8+DR+ TN cells in a sample (e.g., blood) from the subject is increased by about 15% to about 46% (e.g., about 15% to about 31%, about 23% to about 35%, or about 31% to about 46%), as compared to a reference level. In some embodiments, a level of CD8+DR+GzB+ TN cells in a sample (e.g., blood) from the subject is increased by about 27% to about 80% (e.g., about 27% to about 53%, about 40% to about 60%, or about 53% to about 80%), as compared to a reference level. In some embodiments, a level of CD8+DR+KI67+ TN cells in a sample (e.g., blood) from the subject is increased by about 39% to about 116% (e.g., about 39% to about 77%, about 58% to about 87%, or about 77% to about 116%), as compared to a reference level. In some embodiments, a level of CD8+DR+PD1 + TN cells in a sample (e.g., blood) from the subject is increased by about 27% to about 82% (e.g., about 27% to about 54%, about 41 % to about 61%, or about 54% to about 82%), as compared to a reference level. In some embodiments, a level of CD8+GzB+ TN cells in a sample (e.g., blood) from the subject is increased by about 23% to about 69% (e.g., about 23% to about 46%, about 34% to about 52%, or about 46% to about 69%), as compared to a reference level. In some embodiments, a level of CD8+KI67+ TN cells in a sample (e.g., blood) from the subject is increased by about 34% to about 103% (e.g., about 34% to about 69%, about 51% to about 77%, or about 69% to about 103%), as compared to a reference level. In some embodiments, a level of CD8+PD1 + TN cells in a sample (e.g., blood) from the subject is increased by about 11 % to about 32% (e.g., about 11 % to about 21 %, about 16% to about 24%, or about 21 % to about 32%), as compared to a reference level. In some embodiments, a level of CD8+PD1 +OX40+ TN cells in a sample (e.g., blood) from the subject is increased by about 12% to about 37% (e.g., about 12% to about 25%, about 18% to about 28%, or about 25% to about 37%), as compared to a reference level. In some embodiments, a level of CD3-DR+ cells in a sample (e.g., blood) from the subject is increased by about 8% to about 23% (e.g., about 8% to about 15%, about 11 % to about 17%, or about 15% to about 23%), as compared to a reference level. In some embodiments, a level of 0X40+ Treg cells in a sample (e.g., blood) from the subject is increased by about 9% to about 28% (e.g., about 9% to about 19%, about 14% to about 21%, or about 19% to about 28%), as compared to a reference level. In some embodiments, a level of PD1 +OX40+ Treg cells in a sample (e.g., blood) from the subject is increased by about 13% to about 38% (e.g., about 13% to about 25%, about 19% to about 29%, or about 25% to about 38%), as compared to a reference level. In some embodiments, a level of true NK cells in a sample (e.g., blood) from the subject is increased by about 6% to about 18% (e.g., about 6% to about 12%, about 9% to about 13%, or about 12% to about 18%), as compared to a reference level. In some embodiments, a level of white blood cells in a sample (e.g., blood) from the subject is increased by about 2% to about 5% (e.g., about 2% to about 3%, about 3% to about 4%, or about 3% to about 5%), as compared to a reference level. In some embodiments, a level of white blood cells in a sample (e.g., blood) from the subject is increased by about 2% to about 5% (e.g., about 2% to about 3%, about 2% to about 4%, or about 3% to about 5%), as compared to a reference level. In some embodiments, a level of white blood cells in a sample (e.g., blood) from the subject is increased by about 2% to about 7% (e.g., about 2% to about 5%, about 3% to about 5%, or about 5% to about 7%), as compared to a reference level. In some embodiments, a level of white blood cells in a sample (e.g., blood) from the subject is increased by about 2% to about 5% (e.g., about 2% to about 4%, about 3% to about 4%, or about 4% to about 5%), as compared to a reference level.

An MM subject having a decreased level (e.g., presence or percentage) of one or more (e.g., one, two, three, four, five, six, seven, eight, nine, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, or all 80) cell types set forth in Table 8 in a blood sample (e.g., a baseline blood sample), as compared to a reference level, may be identified as one who is likely to benefit from treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab). For example, in some embodiments, a level of CD8+DR+ TCM cells in a sample (e.g., bone marrow) from the subject is decreased by about 6% to about 17% (e.g., about 6% to about 12%, about 9% to about 13%, or about 12% to about 17%), as compared to a reference level. In some embodiments, a level of CD4+DR+ T cells in a sample (e.g., blood) from the subject is decreased by about 8% to about 23% (e.g., about 8% to about 15%, about 11 % to about 17%, or about 15% to about 23%), as compared to a reference level. In some embodiments, a level of CD4+DR+GzB+ T cells in a sample (e.g., blood) from the subject is decreased by about 7% to about 20% (e.g., about 7% to about 14%, about 10% to about 15%, or about 14% to about 20%), as compared to a reference level. In some embodiments, a level of CD4+DR+KI67+ T cells in a sample (e.g., blood) from the subject is decreased by about 10% to about 29% (e.g., about 10% to about 19%, about 15% to about 22%, or about 19% to about 29%), as compared to a reference level. In some embodiments, a level of CD4+DR+PD1 + T cells in a sample (e.g., blood) from the subject is decreased by about 11 % to about 32% (e.g., about 11% to about 21 %, about 16% to about 24%, or about 21 % to about 32%), as compared to a reference level. In some embodiments, a level of CD4+KI67+ T cells in a sample (e.g., blood) from the subject is decreased by about 9% to about 26% (e.g., about 9% to about 17%, about 13% to about 19%, or about 17% to about 26%), as compared to a reference level. In some embodiments, a level of CD4+PD1 + T cells in a sample (e.g., blood) from the subject is decreased by about 5% to about 15% (e.g., about 5% to about 10%, about 8% to about 1 1 %, or about 10% to about 15%), as compared to a reference level. In some embodiments, a level of CD4+PD1 + T cells in a sample (e.g., blood) from the subject is decreased by about 5% to about 16% (e.g., about 5% to about 1 1 %, about 8% to about 12%, or about 1 1 % to about 16%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +KI67+ T cells in a sample (e.g., blood) from the subject is decreased by about 10% to about 31 % (e.g., about 10% to about 21 %, about 15% to about 23%, or about 21 % to about 31 %), as compared to a reference level. In some embodiments, a level of CD4+PD1 +OX40- T cells in a sample (e.g., blood) from the subject is decreased by about 2% to about 6% (e.g., about 2% to about 4%, about 3% to about 4%, or about 4% to about 6%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +0X40+ T cells in a sample (e.g., blood) from the subject is decreased by about 5% to about 14% (e.g., about 5% to about 9%, about 7% to about 10%, or about 9% to about 14%), as compared to a reference level. In some embodiments, a level of CD4+PD1 - TIGIT+TIM3- T cells in a sample (e.g., blood) from the subject is decreased by about 5% to about 14% (e.g., about 5% to about 9%, about 7% to about 10%, or about 9% to about 14%), as compared to a reference level. In some embodiments, a level of CD4+PDL1 + T cells in a sample (e.g., blood) from the subject is decreased by about 6% to about 18% (e.g., about 6% to about 12%, about 9% to about 13%, or about 12% to about 18%), as compared to a reference level. In some embodiments, a level of CD4+TIGIT+ T cells in a sample (e.g., blood) from the subject is decreased by about 5% to about 14% (e.g., about 5% to about 9%, about 7% to about 10%, or about 9% to about 14%), as compared to a reference level. In some embodiments, a level of CD4+DR+ TCM cells in a sample (e.g., blood) from the subject is decreased by about 10% to about 31 % (e.g., about 10% to about 21 %, about 15% to about 23%, or about 21 % to about 31 %), as compared to a reference level. In some embodiments, a level of CD4+DR+KI67+ TCM cells in a sample (e.g., blood) from the subject is decreased by about 10% to about 29% (e.g., about 10% to about 20%, about 15% to about 22%, or about 20% to about 29%), as compared to a reference level. In some embodiments, a level of CD4+DR+PD1 + TCM cells in a sample (e.g., blood) from the subject is decreased by about 14% to about 41 % (e.g., about 14% to about 27%, about 20% to about 30%, or about 27% to about 41 %), as compared to a reference level. In some embodiments, a level of CD4+KI67+ TCM cells in a sample (e.g., blood) from the subject is decreased by about 8% to about 23% (e.g., about 8% to about 15%, about 1 1 % to about 17%, or about 15% to about 23%), as compared to a reference level. In some embodiments, a level of CD4+PD1 + TCM cells in a sample (e.g., blood) from the subject is decreased by about 6% to about 19% (e.g., about 6% to about 12%, about 9% to about 14%, or about 12% to about 19%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +OX40+ TCM cells in a sample (e.g., blood) from the subject is decreased by about 5% to about 15% (e.g., about 5% to about 10%, about 7% to about 1 1 %, or about 10% to about 15%), as compared to a reference level. In some embodiments, a level of CD4+DR+ TEM cells in a sample (e.g., blood) from the subject is decreased by about 5% to about 15% (e.g., about 5% to about 10%, about 8% to about 1 1 %, or about 10% to about 15%), as compared to a reference level. In some embodiments, a level of CD4+DR+KI67+ TEM cells in a sample (e.g., blood) from the subject is decreased by about 8% to about 23% (e.g., about 8% to about 15%, about 1 1 % to about 17%, or about 15% to about 23%), as compared to a reference level. In some embodiments, a level of CD4+DR+PD1 + TEM cells in a sample (e.g., blood) from the subject is decreased by about 7% to about 21 % (e.g., about 7% to about 14%, about 1 1 % to about 16%, or about 14% to about 21 %), as compared to a reference level. In some embodiments, a level of CD4+KI67+ TEM cells in a sample (e.g., blood) from the subject is decreased by about 7% to about 21 % (e.g., about 7% to about 14%, about 1 1 % to about 16%, or about 14% to about 21 %), as compared to a reference level. In some embodiments, a level of CD4+PD1 + TEM cells in a sample (e.g., blood) from the subject is decreased by about 3% to about 10% (e.g., about 3% to about 6%, about 5% to about 7%, or about 6% to about 10%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +OX40+ TEM cells in a sample (e.g., blood) from the subject is decreased by about 3% to about 9% (e.g., about 3% to about 6%, about 5% to about 7%, or about 6% to about 9%), as compared to a reference level. In some embodiments, a level of CD4+DR+ TEMRA cells in a sample (e.g., blood) from the subject is decreased by about 6% to about 18% (e.g., about 6% to about 12%, about 9% to about 14%, or about 12% to about 18%), as compared to a reference level. In some embodiments, a level of CD4+DR+GzB+ TEMRA cells in a sample (e.g., blood) from the subject is decreased by about 5% to about 16% (e.g., about 5% to about 1 1 %, about 8% to about 12%, or about 1 1 % to about 16%), as compared to a reference level. In some embodiments, a level of CD4+DR+KI67+ TEMRA cells in a sample (e.g., blood) from the subject is decreased by about 9% to about 27% (e.g., about 9% to about 18%, about 14% to about 20%, or about 18% to about 27%), as compared to a reference level. In some embodiments, a level of CD4+DR+PD1 + TEMRA cells in a sample (e.g., blood) from the subject is decreased by about 8% to about 25% (e.g., about 8% to about 17%, about 13% to about 19%, or about 17% to about 25%), as compared to a reference level. In some embodiments, a level of CD4+KI67+ TEMRA cells in a sample (e.g., blood) from the subject is decreased by about 8% to about 25% (e.g., about 8% to about 17%, about 13% to about 19%, or about 17% to about 25%), as compared to a reference level. In some embodiments, a level of CD4+PD1 + TEMRA cells in a sample (e.g., blood) from the subject is decreased by about 4% to about 1 1 % (e.g., about 4% to about 7%, about 6% to about 8%, or about 7% to about 1 1 %), as compared to a reference level. In some embodiments, a level of CD4+PD1 +OX40+ TEMRA cells in a sample (e.g., blood) from the subject is decreased by about 4% to about 12% (e.g., about 4% to about 8%, about 6% to about 9%, or about 8% to about 12%), as compared to a reference level. In some embodiments, a level of CD4+DR+ TN cells in a sample (e.g., blood) from the subject is decreased by about 8% to about 23% (e.g., about 8% to about 16%, about 12% to about 17%, or about 16% to about 23%), as compared to a reference level. In some embodiments, a level of CD4+DR+KI67+ TN cells in a sample (e.g., blood) from the subject is decreased by about 15% to about 45% (e.g., about 15% to about 30%, about 23% to about 34%, or about 30% to about 45%), as compared to a reference level. In some embodiments, a level of CD4+DR+PD1 + TN cells in a sample (e.g., blood) from the subject is decreased by about 21 % to about 64% (e.g., about 21 % to about 43%, about 32% to about 48%, or about 43% to about 64%), as compared to a reference level. In some embodiments, a level of CD4+KI67+ TN cells in a sample (e.g., blood) from the subject is decreased by about 1 1 % to about 32% (e.g., about 1 1 % to about 22%, about 16% to about 24%, or about 22% to about 32%), as compared to a reference level. In some embodiments, a level of CD4+PD1 + TN cells in a sample (e.g., blood) from the subject is decreased by about 8% to about 23% (e.g., about 8% to about 15%, about 12% to about 17%, or about 15% to about 23%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +OX40+ TN cells in a sample (e.g., blood) from the subject is decreased by about 7% to about 22% (e.g., about 7% to about 14%, about 1 1 % to about 16%, or about 14% to about 22%), as compared to a reference level. In some embodiments, a level of CD8+DR+ T cells in a sample (e.g., blood) from the subject is decreased by about 3% to about 10% (e.g., about 3% to about 7%, about 5% to about 8%, or about 7% to about 10%), as compared to a reference level. In some embodiments, a level of CD8+DR+GzB+ T cells in a sample (e.g., blood) from the subject is decreased by about 4% to about 1 1 % (e.g., about 4% to about 7%, about 5% to about 8%, or about 7% to about 1 1 %), as compared to a reference level. In some embodiments, a level of CD8+DR+KI67+ T cells in a sample (e.g., blood) from the subject is decreased by about 10% to about 30% (e.g., about 10% to about 20%, about 15% to about 22%, or about 20% to about 30%), as compared to a reference level. In some embodiments, a level of CD8+DR+PD1 + T cells in a sample (e.g., blood) from the subject is decreased by about 6% to about 17% (e.g., about 6% to about 12%, about 9% to about 13%, or about 12% to about 17%), as compared to a reference level. In some embodiments, a level of CD8+GzB+ T cells in a sample (e.g., blood) from the subject is decreased by about 2% to about 7% (e.g., about 2% to about 5%, about 4% to about 6%, or about 5% to about 7%), as compared to a reference level. In some embodiments, a level of CD8+KI67+ T cells in a sample (e.g., blood) from the subject is decreased by about 9% to about 27% (e.g., about 9% to about 18%, about 13% to about 20%, or about 18% to about 27%), as compared to a reference level. In some embodiments, a level of CD8+PD1 + T cells in a sample (e.g., blood) from the subject is decreased by about 4% to about 1 1 % (e.g., about 4% to about 7%, about 5% to about 8%, or about 7% to about 1 1 %), as compared to a reference level. In some embodiments, a level of CD8+PD1 + T cells in a sample (e.g., blood) from the subject is decreased by about 3% to about 10% (e.g., about 3% to about 6%, about 5% to about 7%, or about 6% to about 10%), as compared to a reference level. In some embodiments, a level of CD8+PD1 +GzB+ T cells in a sample (e.g., blood) from the subject is decreased by about 5% to about 14% (e.g., about 5% to about 9%, about 7% to about 10%, or about 9% to about 14%), as compared to a reference level. In some embodiments, a level of CD8+PD1 +KI67+ T cells in a sample (e.g., blood) from the subject is decreased by about 10% to about 31 % (e.g., about 10% to about 21 %, about 16% to about 23%, or about 21 % to about 31 %), as compared to a reference level. In some embodiments, a level of CD8+DR+ TCM cells in a sample (e.g., blood) from the subject is decreased by about 6% to about 17% (e.g., about 6% to about 11%, about 8% to about 13%, or about 11 % to about 17%), as compared to a reference level. In some embodiments, a level of CD8+DR+GzB+ TCM cells in a sample (e.g., blood) from the subject is decreased by about 8% to about 25% (e.g., about 8% to about 16%, about 12% to about 18%, or about 16% to about 25%), as compared to a reference level. In some embodiments, a level of CD8+DR+KI67+ TCM cells in a sample (e.g., blood) from the subject is decreased by about 7% to about 21 % (e.g., about 7% to about 14%, about 11% to about 16%, or about 14% to about 21%), as compared to a reference level. In some embodiments, a level of CD8+DR+PD1 + TCM cells in a sample (e.g., blood) from the subject is decreased by about 7% to about 20% (e.g., about 7% to about 14%, about 10% to about 15%, or about 14% to about 20%), as compared to a reference level. In some embodiments, a level of CD8+GzB+ TCM cells in a sample (e.g., blood) from the subject is decreased by about 7% to about 22% (e.g., about 7% to about 15%, about 11 % to about 16%, or about 15% to about 22%), as compared to a reference level. In some embodiments, a level of CD8+KI67+ TCM cells in a sample (e.g., blood) from the subject is decreased by about 7% to about 20% (e.g., about 7% to about 13%, about 10% to about 15%, or about 13% to about 20%), as compared to a reference level. In some embodiments, a level of CD8+PD1 + TCM cells in a sample (e.g., blood) from the subject is decreased by about 4% to about 13% (e.g., about 4% to about 9%, about 7% to about 10%, or about 9% to about 13%), as compared to a reference level. In some embodiments, a level of CD8+PD1 +0X40+ TCM cells in a sample (e.g., blood) from the subject is decreased by about 6% to about 17% (e.g., about 6% to about 11%, about 9% to about 13%, or about 11% to about 17%), as compared to a reference level. In some embodiments, a level of CD8+DR+ TEM cells in a sample (e.g., blood) from the subject is decreased by about 3% to about 9% (e.g., about 3% to about 6%, about 4% to about 7%, or about 6% to about 9%), as compared to a reference level. In some embodiments, a level of CD8+DR+GzB+ TEM cells in a sample (e.g., blood) from the subject is decreased by about 3% to about 10% (e.g., about 3% to about 6%, about 5% to about 7%, or about 6% to about 10%), as compared to a reference level. In some embodiments, a level of CD8+DR+KI67+ TEM cells in a sample (e.g., blood) from the subject is decreased by about 7% to about 22% (e.g., about 7% to about 15%, about 11 % to about 16%, or about 15% to about 22%), as compared to a reference level. In some embodiments, a level of CD8+DR+PD1 + TEM cells in a sample (e.g., blood) from the subject is decreased by about 5% to about 14% (e.g., about 5% to about 9%, about 7% to about 10%, or about 9% to about 14%), as compared to a reference level. In some embodiments, a level of CD8+GzB+ TEM cells in a sample (e.g., blood) from the subject is decreased by about 2% to about 7% (e.g., about 2% to about 4%, about 3% to about 5%, or about 4% to about 7%), as compared to a reference level. In some embodiments, a level of CD8+KI67+ TEM cells in a sample (e.g., blood) from the subject is decreased by about 6% to about 19% (e.g., about 6% to about 12%, about 9% to about 14%, or about 12% to about 19%), as compared to a reference level. In some embodiments, a level of CD8+PD1 + TEM cells in a sample (e.g., blood) from the subject is decreased by about 2% to about 7% (e.g., about 2% to about 5%, about 4% to about 5%, or about 5% to about 7%), as compared to a reference level. In some embodiments, a level of CD8+DR+ TEMRA cells in a sample (e.g., blood) from the subject is decreased by about 2% to about 7% (e.g., about 2% to about 4%, about 3% to about 5%, or about 4% to about 7%), as compared to a reference level. In some embodiments, a level of CD8+DR+KI67+ TEMRA cells in a sample (e.g., blood) from the subject is decreased by about 9% to about 27% (e.g., about 9% to about 18%, about 14% to about 21 %, or about 18% to about 27%), as compared to a reference level. In some embodiments, a level of CD8+DR+PD1 + TEMRA cells in a sample (e.g., blood) from the subject is decreased by about 5% to about 14% (e.g., about 5% to about 9%, about 7% to about 10%, or about 9% to about 14%), as compared to a reference level. In some embodiments, a level of CD8+GzB+ TEMRA cells in a sample (e.g., blood) from the subject is decreased by about 1 % to about 3% (e.g., about 1 % to about 2%, about 2% to about 2%, or about 2% to about 3%), as compared to a reference level. In some embodiments, a level of CD8+KI67+ TEMRA cells in a sample (e.g., blood) from the subject is decreased by about 9% to about 26% (e.g., about 9% to about 17%, about 13% to about 19%, or about 17% to about 26%), as compared to a reference level. In some embodiments, a level of CD8+PD1 + TEMRA cells in a sample (e.g., blood) from the subject is decreased by about 3% to about 9% (e.g., about 3% to about 6%, about 4% to about 6%, or about 6% to about 9%), as compared to a reference level. In some embodiments, a level of CD8+DR+ TN cells in a sample (e.g., blood) from the subject is decreased by about 6% to about 18% (e.g., about 6% to about 12%, about 9% to about 14%, or about 12% to about 18%), as compared to a reference level. In some embodiments, a level of CD8+DR+GzB+ TN cells in a sample (e.g., blood) from the subject is decreased by about 1 1 % to about 32% (e.g., about 1 1 % to about 21 %, about 16% to about 24%, or about 21 % to about 32%), as compared to a reference level. In some embodiments, a level of CD8+DR+KI67+ TN cells in a sample (e.g., blood) from the subject is decreased by about 15% to about 46% (e.g., about 15% to about 31 %, about 23% to about 35%, or about 31 % to about 46%), as compared to a reference level. In some embodiments, a level of CD8+DR+PD1 + TN cells in a sample (e.g., blood) from the subject is decreased by about 1 1 % to about 33% (e.g., about 1 1 % to about 22%, about 16% to about 24%, or about 22% to about 33%), as compared to a reference level. In some embodiments, a level of CD8+GzB+ TN cells in a sample (e.g., blood) from the subject is decreased by about 9% to about 27% (e.g., about 9% to about 18%, about 14% to about 21 %, or about 18% to about 27%), as compared to a reference level. In some embodiments, a level of CD8+KI67+ TN cells in a sample (e.g., blood) from the subject is decreased by about 14% to about 41 % (e.g., about 14% to about 27%, about 21 % to about 31 %, or about 27% to about 41 %), as compared to a reference level. In some embodiments, a level of CD8+PD1 + TN cells in a sample (e.g., blood) from the subject is decreased by about 4% to about 13% (e.g., about 4% to about 8%, about 6% to about 10%, or about 8% to about 13%), as compared to a reference level. In some embodiments, a level of CD8+PD1 +0X40+ TN cells in a sample (e.g., blood) from the subject is decreased by about 5% to about 15% (e.g., about 5% to about 10%, about 7% to about 1 1 %, or about 10% to about 15%), as compared to a reference level. In some embodiments, a level of CD3-DR+ cells in a sample (e.g., blood) from the subject is decreased by about 3% to about 9% (e.g., about 3% to about 6%, about 5% to about 7%, or about 6% to about 9%), as compared to a reference level. In some embodiments, a level of 0X40+ Treg cells in a sample (e.g., blood) from the subject is decreased by about 4% to about 11% (e.g., about 4% to about 7%, about 6% to about 8%, or about 7% to about 11%), as compared to a reference level. In some embodiments, a level of PD1 +OX40+ Treg cells in a sample (e.g., blood) from the subject is decreased by about 5% to about 15% (e.g., about 5% to about 10%, about 8% to about 11 %, or about 10% to about 15%), as compared to a reference level. In some embodiments, a level of true NK cells in a sample (e.g., blood) from the subject is decreased by about 2% to about 7% (e.g., about 2% to about 5%, about 4% to about 5%, or about 5% to about 7%), as compared to a reference level. In some embodiments, a level of white blood cells in a sample (e.g., blood) from the subject is decreased by about 1% to about 3%, as compared to a reference level.

An MM subject having an increased level (e.g., presence or percentage) of one or more (e.g., one, two, three, four, or all five) cell types set forth in Table 9, as compared to a reference level, may be identified as one who is likely to benefit from treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab). For example, in some embodiments, a level of CD4+ T cells in a sample (e.g., blood) from the subject is increased by about 4% to about 11% (e.g., about 4% to about 7%, about 6% to about 8%, or about 7% to about 11%), as compared to a reference level. In some embodiments, a level of CD4+ T cells in a sample (e.g., blood) from the subject is increased by about 2% to about 7% (e.g., about 2% to about 5%, about 4% to about 6%, or about 5% to about 7%), as compared to a reference level. In some embodiments, a level of CD4+ T cells in a sample (e.g., blood) from the subject is increased by about 4% to about 11% (e.g., about 4% to about 7%, about 5% to about 8%, or about 7% to about 11%), as compared to a reference level. In some embodiments, a level of CD4+ T cells in a sample (e.g., blood) from the subject is increased by about 4% to about 12% (e.g., about 4% to about 8%, about 6% to about 9%, or about 8% to about 12%), as compared to a reference level. In some embodiments, a level of CD8+CD25+CD69- T cells in a sample (e.g., blood) from the subject is increased by about 9% to about 28% (e.g., about 9% to about 18%, about 14% to about 21%, or about 18% to about 28%), as compared to a reference level. In some embodiments, a level of CD8+NK T cells in a sample (e.g., blood) from the subject is increased by about 2% to about 6% (e.g., about 2% to about 4%, about 3% to about 5%, or about 4% to about 6%), as compared to a reference level. In some embodiments, a level of CD8+ TCM cells in a sample (e.g., blood) from the subject is increased by about 7% to about 20% (e.g., about 7% to about 13%, about 10% to about 15%, or about 13% to about 20%), as compared to a reference level. In some embodiments, a level of CD8+ TN cells in a sample (e.g., blood) from the subject is increased by about 5% to about 16% (e.g., about 5% to about 11%, about 8% to about 12%, or about 11% to about 16%), as compared to a reference level. In some embodiments, a level of CD8+ TN cells in a sample (e.g., blood) from the subject is increased by about 6% to about 17% (e.g., about 6% to about 11%, about 8% to about 13%, or about 11 % to about 17%), as compared to a reference level.

An MM subject having a decreased level (e.g., presence or percentage) of one or more (e.g., one, two, three, four, or all five) cell types set forth in Table 9, as compared to a reference level, may be identified as one who is unlikely to benefit from treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab). For example, in some embodiments, a level of CD4+ T cells in a sample (e.g., blood) from the subject is decreased by about 9% to about 28% (e.g., about 9% to about 19%, about 14% to about 21%, or about 19% to about 28%), as compared to a reference level. In some embodiments, a level of CD4+ T cells in a sample (e.g., blood) from the subject is decreased by about 6% to about 19% (e.g., about 6% to about 12%, about 9% to about 14%, or about 12% to about 19%), as compared to a reference level. In some embodiments, a level of CD4+ T cells in a sample (e.g., blood) from the subject is decreased by about 9% to about 27% (e.g., about 9% to about 18%, about 13% to about 20%, or about 18% to about 27%), as compared to a reference level. In some embodiments, a level of CD4+ T cells in a sample (e.g., blood) from the subject is decreased by about 10% to about 30% (e.g., about 10% to about 20%, about 15% to about 22%, or about 20% to about 30%), as compared to a reference level. In some embodiments, a level of CD8+CD25+CD69- T cells in a sample (e.g., blood) from the subject is decreased by about 23% to about 69% (e.g., about 23% to about 46%, about 35% to about 52%, or about 46% to about 69%), as compared to a reference level. In some embodiments, a level of CD8+NK T cells in a sample (e.g., blood) from the subject is decreased by about 5% to about 15% (e.g., about 5% to about 10%, about 8% to about 11%, or about 10% to about 15%), as compared to a reference level. In some embodiments, a level of CD8+ TCM cells in a sample (e.g., blood) from the subject is decreased by about 16% to about 49% (e.g., about 16% to about 33%, about 25% to about 37%, or about 33% to about 49%), as compared to a reference level. In some embodiments, a level of CD8+ TN cells in a sample (e.g., blood) from the subject is decreased by about 13% to about 40% (e.g., about 13% to about 26%, about 20% to about 30%, or about 26% to about 40%), as compared to a reference level. In some embodiments, a level of CD8+ TN cells in a sample (e.g., blood) from the subject is decreased by about 14% to about 42% (e.g., about 14% to about 28%, about 21 % to about 32%, or about 28% to about 42%), as compared to a reference level.

In some aspects of the invention, the method may include the step of measuring or determining a level of 1 or more (e.g., 1 -85), 2 or more (e.g., 2-85), 3 or more (e.g., 3-85), 4 or more (e.g., 4-85), 5 or more (e.g., 5-85), 6 or more (e.g., 6-85), 7 or more (e.g., 7-85), 8 or more (e.g., 8- 85), 9 or more (e.g., 9-85), 10 or more (e.g., 10-85), 11 or more (e.g., 11 -85), 12 or more (e.g., 12-85), 13 or more (e.g., 13-85), 14 or more (e.g., 14-85), 15 or more (e.g., 15-85), 16 or more (e.g., 16-85),

53 or more (e.g., 53-85), 54 or more (e.g., 54-85), 55 or more (e.g., 55-85), 56 or more (e.g., 56-85), 57 or more (e.g., 57-85), 58 or more (e.g., 58-85), 59 or more (e.g., 59-85), 60 or more (e.g., 60-85),

In some aspects of the invention, the method may include the step of measuring or determining 1 or more (e.g., 1 -14), 2 or more (e.g., 2-14), 3 or more (e.g., 3-14), 4 or more (e.g., 4- 14), 5 or more (e.g., 5-14), 6 or more (e.g., 6-14), 7 or more (e.g., 7-14), 8 or more (e.g., 8-14), 9 or more (e.g., 9-14), 10 or more (e.g., 10-14), 1 1 or more (e.g., 1 1 -14), 12 or more (e.g., 12-14), 13 or more (e.g., 13-14), or 14 of the features set forth in Table 5.

In some aspects of the invention, the method may include the step of measuring or determining a level of 1 or more (e.g., 1 -69), 2 or more (e.g., 2-69), 3 or more (e.g., 3-69), 4 or more (e.g., 4-69), 5 or more (e.g., 5-69), 6 or more (e.g., 6-69), 7 or more (e.g., 7-69), 8 or more (e.g., 8- 69), 9 or more (e.g., 9-69), 10 or more (e.g., 10-69), 1 1 or more (e.g., 1 1 -69), 12 or more (e.g., 12-69), 13 or more (e.g., 13-69), 14 or more (e.g., 14-69), 15 or more (e.g., 15-69), 16 or more (e.g., 16-69),

17 or more (e.g., 17-69), 18 or more (e.g., 18-69), 19 or more (e.g., 19-69), 20 or more (e.g., 20-69),

73 or more (e.g., 73-80), 74 or more (e.g., 74-80), 75 or more (e.g., 75-80), 76 or more (e.g., 76-80),

77 or more (e.g., 77-80), 78 or more (e.g., 78-80), 79 or more (e.g., 79-80), or 80 of the cell types set forth in Table 8.

A method of identifying the subject having an MM as one who would benefit from a treatment comprising a bispecific antibody that binds to FcRH5 and CD3 may further include a subsequent step of administering to the identified subject the treatment comprising the bispecific antibody that binds to FcRH5 and CD3. Any step of administering the bispecific antibody that binds to FcRH5 and CD3 may be performed using the dosing regimens described herein.

B. Methods of classifying

In some aspects, the invention provides a method of classifying an MM in a subject (e.g., a subject having an R/R MM). The method of classifying may include a step of determining or measuring a level of CD8+ T cells, Treg cells, and CD8+ TN cells in a sample (e.g., blood or bone marrow) from the subject. The method of classifying may further include a step of assigning (e.g., by similarity network fusion (SNF)) the subject’s MM to one of the following immune profiles based on the level of the CD8+ T cells, Treg cells, and CD8+ TN cells: (a) an activated immune profile; (b) an inactivated immune profile; or (c) a suppressed immune profile, thereby classifying the MM in the subject. In some aspects, the activated immune profile has an increased level of CD8+ T cells, a decreased level of Treg cells, and a decreased level of CD8+ TN cells in the sample (e.g., blood or bone marrow) from the subject, as compared to a reference level. In some aspects the inactivated immune profile has a decreased level of CD8+ T cells, an increased level of Treg cells, and an increased level of CD8+ TN cells in the sample (e.g., blood or bone marrow) from the subject, as compared to a reference level. In some aspects, the suppressed immune profile comprises an increased level of CD8+ T cells, an increased level of Treg cells, and a decreased level of CD8+ TN cells, in the sample (e.g., blood or bone marrow) from the subject, as compared to a reference level.

In some aspects, the method of classifying may further include a step of determining a level of one or more additional cell types set forth in Table 3 in a sample (e.g., blood or bone marrow) from the subject, a level of one or more additional cell types set forth in Table 4 in a sample (e.g., blood or bone marrow) from the subject, and/or one or more of the features set forth in Table 5 of the subject. The subject’s MM may then be assigned (e.g., by SNF) to one of the following immune profiles based on (i) the level of the CD8+ T cells, Treg cells, and CD8+ TN cells, and (ii) the level of one or more additional cell types set forth in Table 3, the level of one or more additional cell types set forth in Table 4, and/or the one or more of the features set forth in Table 5: (a) an activated immune profile; (b) an inactivated immune profile; or (c) a suppressed immune profile, thereby classifying the MM in the subject.

In some aspects, the method of classifying may further include a step of determining a level of one or more additional cell types set forth in Table 6 in a sample (e.g., blood or bone marrow) from the subject and/or a level of one or more additional cell types set forth in Table 7 in a sample (e.g., blood or bone marrow) from the subject. The subject’s MM may then be assigned (e.g., by SNF) to one of the following immune profiles based on (i) the level of the CD8+ T cells, Treg cells, and CD8+ TN cells, and (ii) the level of one or more additional cell types set forth in Table 6 and/or Table 7: (a) an activated immune profile; (b) an inactivated immune profile; or (c) a suppressed immune profile, thereby classifying the MM in the subject.

In some aspects, the method of classifying may further include a step of determining a level of one or more additional cell types set forth in Table 8 in a sample (e.g., blood or bone marrow) from the subject and/or a level of one or more additional cell types set forth in Table 9 in a sample (e.g., blood or bone marrow) from the subject. The subject’s MM may then be assigned (e.g., by SNF) to one of the following immune profiles based on (i) the level of the CD8+ T cells, Treg cells, and CD8+ TN cells, and (ii) the level of one or more additional cell types set forth in Table 8 and/or Table 9: (a) an activated immune profile; (b) an inactivated immune profile; or (c) a suppressed immune profile, thereby classifying the MM in the subject.

In some aspects, the one or more additional cell types may include one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, 10 or more, 11 or more, 12 or more, 13 or more, 14 or more, 15 or more, 16 or more, 17 or more, 18 or more, 19 or more, 20 or more, 21 or more, 22 or more, 23 or more, 24 or more, 25 or more, 26 or more, 27 or more, 28 or more, 29 or more, 30 or more, 31 or more, 32 or more, 33 or more, 34 or more, 35 or more, 36 or more, 37 or more, 38 or more, 39 or more, 40 or more, 41 or more, 42 or more, 43 or more, 44 or more, 45 or more, 46 or more, 47 or more, 48 or more, 49 or more, 50 or more, 51 or more, 52 or more, 53 or more, 54 or more, 55 or more, 56 or more, 57 or more, 58 or more, 59 or more, 60 or more, 61 or more, 62 or more, 63 or more, 64 or more, 65 or more, 66 or more, 67 or more, 68 or more, 69 or more, 70 or more, 71 or more, 72 or more, 73 or more, 74 or more, 75 or more, 76 or more, 77 or more, 78 or more, 79 or more, 80 or more, 81 or more, 82 or more, 83 or more, 84 or more, or all 85 cell types set forth in Table 3.

In some aspects, the one or more additional cell types may include one or more, two or more, three or more, four or more, five or more, six or more, seven or more, or all eight cell types set forth in Table 4.

In some aspects, the one or more additional cell types may include one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, 10 or more, 11 or more, 12 or more, 13 or more, or all 14 features set forth in Table 5. In some aspects, the one or more additional cell types may include one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, 10 or more, 11 or more, 12 or more, 13 or more, 14 or more, 15 or more, 16 or more, 17 or more, 18 or more, 19 or more, 20 or more, 21 or more, 22 or more, 23 or more, 24 or more, 25 or more, 26 or more, 27 or more, 28 or more, 29 or more, 30 or more, 31 or more, 32 or more, 33 or more, 34 or more, 35 or more, 36 or more, 37 or more, 38 or more, 39 or more, 40 or more, 41 or more, 42 or more, 43 or more, 44 or more, 45 or more, 46 or more, 47 or more, 48 or more, 49 or more, 50 or more, 51 or more, 52 or more, 53 or more, 54 or more, 55 or more, 56 or more, 57 or more, 58 or more, 59 or more, 60 or more, 61 or more, 62 or more, 63 or more, 64 or more, 65 or more, 66 or more, 67 or more, 68 or more, or all 69 cell types set forth in Table 6.

In some aspects, the one or more additional cell types may include one or more, two or more, three or more, four or more, five or more, six or more, seven or more, or all eight cell types set forth in Table 7.

In some aspects, the one or more additional cell types may include one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, 10 or more, 11 or more, 12 or more, 13 or more, 14 or more, 15 or more, 16 or more, 17 or more, 18 or more, 19 or more, 20 or more, 21 or more, 22 or more, 23 or more, 24 or more, 25 or more, 26 or more, 27 or more, 28 or more, 29 or more, 30 or more, 31 or more, 32 or more, 33 or more, 34 or more, 35 or more, 36 or more, 37 or more, 38 or more, 39 or more, 40 or more, 41 or more, 42 or more, 43 or more, 44 or more, 45 or more, 46 or more, 47 or more, 48 or more, 49 or more, 50 or more, 51 or more, 52 or more, 53 or more, 54 or more, 55 or more, 56 or more, 57 or more, 58 or more, 59 or more, 60 or more, 61 or more, 62 or more, 63 or more, 64 or more, 65 or more, 66 or more, 67 or more, 68 or more, 69 or more, 70 or more, 71 or more, 72 or more, 73 or more, 74 or more, 75 or more, 76 or more, 77 or more, 78 or more, 79 or more, or all 80 cell types set forth in Table 8.

In some aspects, the one or more additional cell types may include one or more, two or more, three or more, four or more or all five cell types set forth in Table 9.

In some aspects, subjects classified as having an activated immune profile or an inactivated immune profile may benefit from treatment with a bispecific antibody that binds to FcRH5 and CD3. In some aspects, if the subject has a decreased level of the one or more additional cell types set forth in Table 3, Table 6, and/or Table 8, as compared to a reference level; an increased level of the one or more cell types set forth in Table 4, Table 7 and/or Table 9, as compared to a reference level; and/or a lower number in one or more of the features set forth in Table 5, as compared to a reference number, then the subject can be identified as one who would benefit from the treatment comprising the bispecific antibody that binds to FcRH5 and CD3. A subject may benefit from the treatment with the bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) when the subject exhibits a relative increase in overall survival (OS), objective response rate (ORR), progression-free survival (PFS), complete response (CR), partial response (PR), or a combination thereof. In some aspects, the reference level is a pre-assigned reference level set forth in Table 14. In some aspects, the reference number is a pre-assigned reference number set forth in Table 15.

The sample from the subject may be from the subject’s bone marrow and/or blood. Flow cytometry (FC), mass spectrometry (MS), immunohistochemistry (IHC), DNA sequencing (DNA-seq), RNA sequencing (RNA-seq), quantitative PCR (qPCR), reverse transcription-quantitative polymerase chain reaction (RT-qPCR), multiplex qPCR or RT-qPCR, microarray analysis, serial analysis of gene expression (SAGE), MASSARRAY® technique, in situ hybridization (ISH), or a combination thereof, may be used to determine the level of the CD8+ T cells, the Treg cells, the CD8+ TN cells, and/or the one or more additional cell types in the sample (e.g., bone marrow or blood).

In any of the foregoing methods of classifying, additional steps of identifying the subject and/or treating the subject, as described herein, may be included in the classifying method.

IV. Bispecific Anti-FcRH5/Anti-CD3 Antibodies

The methods described herein include administering to a subject having a cancer (e.g., a multiple myeloma, e.g., an R/R multiple myeloma) a bispecific antibody that binds to FcRH5 and CD3 (i.e., a bispecific anti-FcRH5/anti-CD3 antibody).

In some instances, any of the methods described herein may include administering a bispecific antibody that includes an anti-FcRH5 arm having a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) an HVR-H1 comprising the amino acid sequence of RFGVH (SEQ ID NO: 1 ); (b) an HVR-H2 comprising the amino acid sequence of VIWRGGSTDYNAAFVS (SEQ ID NO: 2); (c) an HVR-H3 comprising the amino acid sequence of HYYGSSDYALDN (SEQ ID NO:3); (d) an HVR-L1 comprising the amino acid sequence of KASQDVRNLVV (SEQ ID NO: 4); (e) an HVR-L2 comprising the amino acid sequence of SGSYRYS (SEQ ID NO: 5); and (f) an HVR-L3 comprising the amino acid sequence of QQHYSPPYT (SEQ ID NO: 6). In some instances, the bispecific anti-FcRH5/anti-CD3 antibody comprises at least one (e.g., 1 , 2, 3, or 4) of the heavy chain framework regions FR-H1 , FR-H2, FR-H3, and FR-H4 comprising the sequences of SEQ ID NOs: 17-20, respectively, and/or at least one (e.g., 1 , 2, 3, or 4) of the light chain framework regions FR-L1 , FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQ ID NOs: 21 -24, respectively.

In some instances, any of the methods described herein may include administering a bispecific antibody that includes an anti-FcRH5 arm having a first binding domain comprising the following six HVRs: (a) an HVR-H1 comprising the amino acid sequence of RFGVH (SEQ ID NO: 1 ); (b) an HVR-H2 comprising the amino acid sequence of VIWRGGSTDYNAAFVS (SEQ ID NO: 2); (c) an HVR-H3 comprising the amino acid sequence of HYYGSSDYALDN (SEQ ID NO:3); (d) an HVR- L1 comprising the amino acid sequence of KASQDVRNLVV (SEQ ID NO: 4); (e) an HVR-L2 comprising the amino acid sequence of SGSYRYS (SEQ ID NO: 5); and (f) an HVR-L3 comprising the amino acid sequence of QQHYSPPYT (SEQ ID NO: 6). In some instances, the bispecific anti- FcRH5/anti-CD3 antibody comprises at least one (e.g., 1 , 2, 3, or 4) of the heavy chain framework regions FR-H1 , FR-H2, FR-H3, and FR-H4 comprising the sequences of SEQ ID NOs: 17-20, respectively, and/or at least one (e.g., 1 , 2, 3, or 4) of the light chain framework regions FR-L1 , FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQ ID NOs: 21 -24, respectively.

In some instances, the bispecific antibody comprises an anti-FcRH5 arm comprising a first binding domain comprising (a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 7; (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 8; or (c) a VH domain as in (a) and a VL domain as in (b). Accordingly, in some instances, the first binding domain comprises a VH domain comprising an amino acid sequence of SEQ ID NO: 7 and a VL domain comprising an amino acid sequence of SEQ ID NO: 8.

In some instances, any of the methods described herein may include administering a bispecific anti-FcRH5/anti-CD3 antibody that includes an anti-CD3 arm having a second binding domain comprising at least one, two, three, four, five, or six HVRs selected from (a) an HVR-H1 comprising the amino acid sequence of SYYIH (SEQ ID NO: 9); (b) an HVR-H2 comprising the amino acid sequence of WIYPENDNTKYNEKFKD (SEQ ID NO: 10); (c) an HVR-H3 comprising the amino acid sequence of DGYSRYYFDY (SEQ ID NO: 11 ); (d) an HVR-L1 comprising the amino acid sequence of KSSQSLLNSRTRKNYLA (SEQ ID NO: 12); (e) an HVR-L2 comprising the amino acid sequence of WTSTRKS (SEQ ID NO: 13); and (f) an HVR-L3 comprising the amino acid sequence of KQSFILRT (SEQ ID NO: 14). In some instances, the anti-FcRH5/anti-CD3 bispecific antibody comprises at least one (e.g., 1 , 2, 3, or 4) of heavy chain framework regions FR-H1 , FR-H2, FR-H3, and FR-H4 comprising the sequences of SEQ ID NOs: 25-28, respectively, and/or at least one (e.g., 1 , 2, 3, or 4) of the light chain framework regions FR-L1 , FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQ ID NOs: 29-32, respectively.

In some instances, any of the methods described herein may include administering a bispecific anti-FcRH5/anti-CD3 antibody that includes an anti-CD3 arm having a second binding domain comprising the following six HVRs: (a) an HVR-H1 comprising the amino acid sequence of SYYIH (SEQ ID NO: 9); (b) an HVR-H2 comprising the amino acid sequence of WIYPENDNTKYNEKFKD (SEQ ID NO: 10); (c) an HVR-H3 comprising the amino acid sequence of DGYSRYYFDY (SEQ ID NO: 11 ); (d) an HVR-L1 comprising the amino acid sequence of KSSQSLLNSRTRKNYLA (SEQ ID NO: 12); (e) an HVR-L2 comprising the amino acid sequence of WTSTRKS (SEQ ID NO: 13); and (f) an HVR-L3 comprising the amino acid sequence of KQSFILRT (SEQ ID NO: 14). In some instances, the anti-FcRH5/anti-CD3 bispecific antibody comprises at least one (e.g., 1 , 2, 3, or 4) of heavy chain framework regions FR-H1 , FR-H2, FR-H3, and FR-H4 comprising the sequences of SEQ ID NOs: 25-28, respectively, and/or at least one (e.g., 1 , 2, 3, or 4) of the light chain framework regions FR-L1 , FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQ ID NOs: 29-32, respectively.

In some instances, the bispecific antibody comprises an anti-CD3 arm comprising a second binding domain comprising (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 15; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 16; or (c) a VH domain as in (a) and a VL domain as in (b). Accordingly, in some instances, the second binding domain comprises a VH domain comprising an amino acid sequence of SEQ ID NO: 15 and a VL domain comprising an amino acid sequence of SEQ ID NO: 16.

In some instances, any of the methods described herein may include administering a bispecific antibody that includes (1 ) an anti-FcRH5 arm having a first binding domain comprising at least one, two, three, four, five, or six HVRs selected from (a) an HVR-H1 comprising the amino acid sequence of RFGVH (SEQ ID NO: 1 ); (b) an HVR-H2 comprising the amino acid sequence of VIWRGGSTDYNAAFVS (SEQ ID NO: 2); (c) an HVR-H3 comprising the amino acid sequence of HYYGSSDYALDN (SEQ ID NO:3); (d) an HVR-L1 comprising the amino acid sequence of KASQDVRNLVV (SEQ ID NO: 4); (e) an HVR-L2 comprising the amino acid sequence of SGSYRYS (SEQ ID NO: 5); and (f) an HVR-L3 comprising the amino acid sequence of QQHYSPPYT (SEQ ID NO: 6) and (2) an anti-CD3 arm having a second binding domain comprising at least one, two, three, four, five, or six HVRs selected from (a) an HVR-H1 comprising the amino acid sequence of SYYIH (SEQ ID NO: 9); (b) an HVR-H2 comprising the amino acid sequence of WIYPENDNTKYNEKFKD (SEQ ID NO: 10); (c) an HVR-H3 comprising the amino acid sequence of DGYSRYYFDY (SEQ ID NO: 11 ); (d) an HVR-L1 comprising the amino acid sequence of KSSQSLLNSRTRKNYLA (SEQ ID NO: 12); (e) an HVR-L2 comprising the amino acid sequence of WTSTRKS (SEQ ID NO: 13); and (f) an HVR-L3 comprising the amino acid sequence of KQSFILRT (SEQ ID NO: 14).

In some instances, any of the methods described herein may include administering a bispecific antibody that includes (1 ) an anti-FcRH5 arm having a first binding domain comprising the following six HVRs: (a) an HVR-H1 comprising the amino acid sequence of RFGVH (SEQ ID NO: 1 ); (b) an HVR-H2 comprising the amino acid sequence of VIWRGGSTDYNAAFVS (SEQ ID NO: 2); (c) an HVR-H3 comprising the amino acid sequence of HYYGSSDYALDN (SEQ ID NO:3); (d) an HVR- L1 comprising the amino acid sequence of KASQDVRNLVV (SEQ ID NO: 4); (e) an HVR-L2 comprising the amino acid sequence of SGSYRYS (SEQ ID NO: 5); and (f) an HVR-L3 comprising the amino acid sequence of QQHYSPPYT (SEQ ID NO: 6) and (2) an anti-CD3 arm having a second binding domain comprising the following six HVRs: (a) an HVR-H1 comprising the amino acid sequence of SYYIH (SEQ ID NO: 9); (b) an HVR-H2 comprising the amino acid sequence of WIYPENDNTKYNEKFKD (SEQ ID NO: 10); (c) an HVR-H3 comprising the amino acid sequence of DGYSRYYFDY (SEQ ID NO: 11 ); (d) an HVR-L1 comprising the amino acid sequence of KSSQSLLNSRTRKNYLA (SEQ ID NO: 12); (e) an HVR-L2 comprising the amino acid sequence of WTSTRKS (SEQ ID NO: 13); and (f) an HVR-L3 comprising the amino acid sequence of KQSFILRT (SEQ ID NO: 14).

In some instances, the anti-FcRH5/anti-CD3 bispecific antibody comprises (1 ) at least one (e.g., 1 , 2, 3, or 4) of heavy chain framework regions FR-H1 , FR-H2, FR-H3, and FR-H4 comprising the sequences of SEQ ID NOs: 17-20, respectively, and/or at least one (e.g., 1 , 2, 3, or 4) of the light chain framework regions FR-L1 , FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQ ID NOs: 21 -24, respectively, and (2) at least one (e.g., 1 , 2, 3, or 4) of heavy chain framework regions FR-H1 , FR-H2, FR-H3, and FR-H4 comprising the sequences of SEQ ID NOs: 25-28, respectively, and/or at least one (e.g., 1 , 2, 3, or 4) of the light chain framework regions FR-L1 , FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQ ID NOs: 29-32, respectively. In some instances, the anti- FcRH5/anti-CD3 bispecific antibody comprises (1 ) all four of heavy chain framework regions FR-H1 , FR-H2, FR-H3, and FR-H4 comprising the sequences of SEQ ID NOs: 17-20, respectively, and/or all four of the light chain framework regions FR-L1 , FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQ ID NOs: 21 -24, respectively, and (2) all four of heavy chain framework regions FR-H1 , FR-H2, FR-H3, and FR-H4 comprising the sequences of SEQ ID NOs: 25-28, respectively, and/or all four (e.g., 1 , 2, 3, or 4) of the light chain framework regions FR-L1 , FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQ ID NOs: 29-32, respectively.

In some instances, the anti-FcRH5/anti-CD3 bispecific antibody comprises (1 ) an anti-FcRH5 arm comprising a first binding domain comprising (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 7; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 8; or (c) a VH domain as in (a) and a VL domain as in (b), and (2) an anti-CD3 arm comprising a second binding domain comprising (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 15; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 16; or (c) a VH domain as in (a) and a VL domain as in (b). In some instances, the anti-FcRH5/anti-CD3 bispecific antibody comprises (1 ) a first binding domain comprising a VH domain comprising an amino acid sequence of SEQ ID NO: 7 and a VL domain comprising an amino acid sequence of SEQ ID NO: 8 and (2) a second binding domain comprising a VH domain comprising an amino acid sequence of SEQ ID NO: 15 and a VL domain comprising an amino acid sequence of SEQ ID NO: 16.

In some instances, the anti-FcRH5/anti-CD3 bispecific antibody comprises an anti-FcRH5 arm comprising a heavy chain polypeptide (H1 ) and a light chain polypeptide (L1 ), wherein (a) H1 comprises an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 35 and/or (b) L1 comprises an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 36.

In some instances, the anti-FcRH5/anti-CD3 bispecific antibody comprises an anti-FcRH5 arm comprising a heavy chain polypeptide (H1 ) and a light chain polypeptide (L1 ), wherein (a) H1 comprises the amino acid sequence of SEQ ID NO: 35 and/or (b) L1 comprises the amino acid sequence of SEQ ID NO: 36.

In some instances, the anti-FcRH5/anti-CD3 bispecific antibody comprises an anti-CD3 arm comprising a heavy chain polypeptide (H2) and a light chain polypeptide (L2), wherein (a) H2 comprises an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 37 and/or (b) L2 comprises an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 38.

In some instances, the anti-FcRH5/anti-CD3 bispecific antibody comprises an anti-CD3 arm comprising a heavy chain polypeptide (H2) and a light chain polypeptide (L2), wherein (a) H2 comprises the amino acid sequence of SEQ ID NO: 37; and (b) L2 comprises the amino acid sequence of SEQ ID NO: 38.

In some instances, the anti-FcRH5/anti-CD3 bispecific antibody comprises an anti-FcRH5 arm comprising a heavy chain polypeptide (H1 ) and a light chain polypeptide (L1 ) and an anti-CD3 arm comprising a heavy chain polypeptide (H2) and a light chain polypeptide (L2), and wherein (a) H1 comprises an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 35; (b) L1 comprises an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 36; (c) H2 comprises an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 37; and (d) L2 comprises an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 38.

In some instances, the anti-FcRH5/anti-CD3 bispecific antibody comprises an anti-FcRH5 arm comprising a heavy chain polypeptide (H1 ) and a light chain polypeptide (L1 ) and an anti-CD3 arm comprising a heavy chain polypeptide (H2) and a light chain polypeptide (L2), and wherein (a) H1 comprises the amino acid sequence of SEQ ID NO: 35; (b) L1 comprises the amino acid sequence of SEQ ID NO: 36; (c) H2 comprises the amino acid sequence of SEQ ID NO: 37; and (d) L2 comprises the amino acid sequence of SEQ ID NO: 38.

In some instances, the anti-FcRH5/anti-CD3 bispecific antibody is cevostamab.

In some instances, the anti-FcRH5/anti-CD3 bispecific antibody according to any of the above embodiments described above may incorporate any of the features, singly or in combination, as described in Sections 1 -6 below.

1. Antibody affinity

In certain embodiments, a bispecific anti-FcRH5/anti-CD3 antibody provided herein has a dissociation constant (KD) of < 1 pM, < 250 nM, < 100 nM, < 15 nM, < 10 nM, < 6 nM, < 4 nM, < 2 nM, < 1 nM, < 0.1 nM, < 0.01 nM, or < 0.001 nM (e.g. 10⁸ M or less, e.g., from 10⁸ M to 10¹³ M, e.g., from 10'⁹ M to 10'¹³ M) for FcRH5 and/or CD3.

In one embodiment, KD is measured by a radiolabeled antigen binding assay (RIA). In one embodiment, an RIA is performed with the Fab version of an antibody of interest and its antigen. For example, solution binding affinity of Fabs for antigen is measured by equilibrating Fab with a minimal concentration of (¹²⁵l)-labeled antigen in the presence of a titration series of unlabeled antigen, then capturing bound antigen with an anti-Fab antibody-coated plate (see, e.g., Chen et al., J. Mol. Biol. 293:865-881 (1999)). To establish conditions for the assay, MICROTITER® multi-well plates (Thermo Scientific) are coated overnight with 5 pg/ml of a capturing anti-Fab antibody (Cappel Labs) in 50 mM sodium carbonate (pH 9.6), and subsequently blocked with 2% (w/v) bovine serum albumin in PBS for two to five hours at room temperature (approximately 23°C). In a non-adsorbent plate (Nunc #269620), 100 pM or 26 pM [¹²⁵l]-antigen are mixed with serial dilutions of a Fab of interest (e.g., consistent with assessment of the anti-VEGF antibody, Fab-12, in Presta et al., Cancer Res. 57:4593- 4599 (1997)). The Fab of interest is then incubated overnight; however, the incubation may continue for a longer period (e.g., about 65 hours) to ensure that equilibrium is reached. Thereafter, the mixtures are transferred to the capture plate for incubation at room temperature (e.g., for one hour). The solution is then removed and the plate washed eight times with 0.1 % polysorbate 20 (TWEEN- 20®) in PBS. When the plates have dried, 150 pl/well of scintillant (MICROSCINT-20 ™; Packard) is added, and the plates are counted on a TOPCOUNT ™ gamma counter (Packard) for ten minutes. Concentrations of each Fab that give less than or equal to 20% of maximal binding are chosen for use in competitive binding assays.

According to another embodiment, KD is measured using a BIACORE® surface plasmon resonance assay. For example, an assay using a BIACORE®-2000 or a BIACORE ®-3000 (BIAcore, Inc., Piscataway, NJ) is performed at 37°C with immobilized antigen CM5 chips at -10 response units (RU). In one embodiment, carboxymethylated dextran biosensor chips (CM5, BIACORE, Inc.) are activated with A/-ethyl- N (3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC) and N- hydroxysuccinimide (NHS) according to the supplier’s instructions. Antigen is diluted with 10 mM sodium acetate, pH 4.8, to 5 pg/ml (~0.2 pM) before injection at a flow rate of 5 pl/minute to achieve approximately 10 response units (RU) of coupled protein. Following the injection of antigen, 1 M ethanolamine is injected to block unreacted groups. For kinetics measurements, two-fold serial dilutions of Fab (0.78 nM to 500 nM) are injected in PBS with 0.05% polysorbate 20 (TWEEN-20™) surfactant (PBST) at 37°C at a flow rate of approximately 25 pl/min. Association rates (k_On, or k_a) and dissociation rates (k_otf, or kd) are calculated using a simple one-to-one Langmuir binding model (BIACORE ® Evaluation Software version 3.2) by simultaneously fitting the association and dissociation sensorgrams. The equilibrium dissociation constant (KD) is calculated as the ratio kotf/kon. See, for example, Chen et al., J. Mol. Biol. 293:865-881 (1999). If the on-rate exceeds 10⁶M'¹s‘¹ by the surface plasmon resonance assay above, then the on-rate can be determined by using a fluorescent quenching technique that measures the increase or decrease in fluorescence emission intensity (excitation = 295 nm; emission = 340 nm, 16 nm band-pass) at 37°C of a 20 nM anti-antigen antibody (Fab form) in PBS, pH 7.2, in the presence of increasing concentrations of antigen as measured in a spectrometer, such as a stop-flow equipped spectrophotometer (Aviv Instruments) or a 8000-series SLM-AMINCO™ spectrophotometer (ThermoSpectronic) with a stirred cuvette.

2. Antibody fragments

In certain embodiments, a bispecific anti-FcRH5/anti-CD3 antibody provided herein is an antibody fragment that binds FcRH5 and CD3. Antibody fragments include, but are not limited to, Fab, Fab’, Fab’-SH, F(ab’)2, Fv, and scFv fragments, and other fragments described below. For a review of certain antibody fragments, see Hudson et al. Nat. Med. 9:129-134 (2003). For a review of scFv fragments, see, e.g., Pluckthun, in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., (Springer-Verlag, New York), pp. 269-315 (1994); see also WO 93/16185; and U.S. Patent Nos. 5,571 ,894 and 5,587,458. For discussion of Fab and F(ab’)2 fragments comprising salvage receptor binding epitope residues and having increased in vivo half-life, see U.S. Patent No. 5,869,046.

Diabodies are antibody fragments with two antigen-binding sites that may be bivalent or bispecific. See, for example, EP 404,097; WO 1993/01161 ; Hudson et al. Nat. Med. 9:129-134 (2003); and Hollinger et al. Proc. Natl. Acad. Sci. USA 90: 6444-6448 (1993). Triabodies and tetrabodies are also described in Hudson et al. Nat. Med. 9:129-134 (2003).

Single-domain antibodies are antibody fragments comprising all or a portion of the heavy chain variable domain or all or a portion of the light chain variable domain of an antibody. In certain embodiments, a single-domain antibody is a human single-domain antibody (Domantis, Inc., Waltham, MA; see, e.g., U.S. Patent No. 6,248,516 B1 ).

Antibody fragments can be made by various techniques, including but not limited to proteolytic digestion of an intact antibody as well as production by recombinant host cells (e.g. E. coll or phage), as described herein.

3. Chimeric and humanized antibodies

In certain embodiments, a bispecific anti-FcRH5/anti-CD3 antibody provided herein is a chimeric antibody. Certain chimeric antibodies are described, e.g., in U.S. Patent No. 4,816,567; and Morrison et al. Proc. Natl. Acad. Sci. USA, 81 :6851 -6855 (1984)). In one example, a chimeric antibody comprises a non-human variable region (e.g., a variable region derived from a mouse, rat, hamster, rabbit, or non-human primate, such as a monkey) and a human constant region. In a further example, a chimeric antibody is a “class switched” antibody in which the class or subclass has been changed from that of the parent antibody. Chimeric antibodies include antigen-binding fragments thereof.

In certain embodiments, a chimeric antibody is a humanized antibody. Typically, a non- human antibody is humanized to reduce immunogenicity to humans, while retaining the specificity and affinity of the parental non-human antibody. Generally, a humanized antibody comprises one or more variable domains in which HVRs (or portions thereof), for example, are derived from a non-human antibody, and FRs (or portions thereof) are derived from human antibody sequences. A humanized antibody optionally will also comprise at least a portion of a human constant region. In some embodiments, some FR residues in a humanized antibody are substituted with corresponding residues from a non-human antibody (e.g., the antibody from which the HVR residues are derived), e.g., to restore or improve antibody specificity or affinity.

Humanized antibodies and methods of making them are reviewed, e.g., in Almagro and Fransson, Front. Biosci. 13:1619-1633 (2008), and are further described, e.g., in Riechmann et al., Nature 332:323-329 (1988); Queen et al., Proc. Nat’l Acad. Sci. USA 86:10029-10033 (1989); US Patent Nos. 5, 821 ,337, 7,527,791 , 6,982,321 , and 7,087,409; Kashmiri et al., Methods 36:25-34 (2005) (describing specificity determining region (SDR) grafting); Padlan, Mol. Immunol. 28:489-498 (1991 ) (describing “resurfacing”); Dall’Acqua et al., Methods 36:43-60 (2005) (describing “FR shuffling”); and Osbourn et al., Methods 36:61 -68 (2005) and Klimka et al., Br. J. Cancer, 83:252-260 (2000) (describing the “guided selection” approach to FR shuffling).

Human framework regions that may be used for humanization include but are not limited to: framework regions selected using the “best-fit” method (see, e.g., Sims et al. J. Immunol. 151 :2296 (1993)); framework regions derived from the consensus sequence of human antibodies of a particular subgroup of light or heavy chain variable regions (see, e.g., Carter et al. Proc. Natl. Acad. Sci. USA, 89:4285 (1992); and Presta et al. J. Immunol., 151 :2623 (1993)); human mature (somatically mutated) framework regions or human germline framework regions (see, e.g., Almagro and Fransson, Front. Biosci. 13:1619-1633 (2008)); and framework regions derived from screening FR libraries (see, e.g., Baca et al., J. Biol. Chem. 272:10678-10684 (1997) and Rosok et al., J. Biol. Chem. 271 :22611 - 22618 (1996)).

4. Human antibodies

In certain embodiments, a bispecific anti-FcRH5/anti-CD3 antibody provided herein is a human antibody. Human antibodies can be produced using various techniques known in the art. Human antibodies are described generally in van Dijk and van de Winkel, Curr. Opin. Pharmacol. 5: 368-74 (2001 ) and Lonberg, Curr. Opin. Immunol. 20:450-459 (2008).

Human antibodies may be prepared by administering an immunogen to a transgenic animal that has been modified to produce intact human antibodies or intact antibodies with human variable regions in response to antigenic challenge. Such animals typically contain all or a portion of the human immunoglobulin loci, which replace the endogenous immunoglobulin loci, or which are present extrachromosomally or integrated randomly into the animal’s chromosomes. In such transgenic mice, the endogenous immunoglobulin loci have generally been inactivated. For review of methods for obtaining human antibodies from transgenic animals, see Lonberg, Nat. Biotech. 23:1117-1125 (2005). See also, e.g., U.S. Patent Nos. 6,075,181 and 6,150,584 describing XENOMOUSE™ technology; U.S. Patent No. 5,770,429 describing HUMAB® technology; U.S. Patent No. 7,041 ,870 describing K-M MOUSE® technology, and U.S. Patent Application Publication No. US 2007/0061900, describing VELOCIMOUSE® technology). Human variable regions from intact antibodies generated by such animals may be further modified, e.g., by combining with a different human constant region.

Human antibodies can also be made by hybridoma-based methods. Human myeloma and mouse-human heteromyeloma cell lines for the production of human monoclonal antibodies have been described. (See, e.g., Kozbor J. Immunol., 133: 3001 (1984); Brodeur et al., Monoclonal Antibody Production Techniques and Applications, pp. 51 -63 (Marcel Dekker, Inc., New York, 1987); and Boerner et al., J. Immunol., 147: 86 (1991 ).) Human antibodies generated via human B-cell hybridoma technology are also described in Li et al., Proc. Natl. Acad. Sci. USA, 103:3557-3562 (2006). Additional methods include those described, for example, in U.S. Patent No. 7,189,826 (describing production of monoclonal human IgM antibodies from hybridoma cell lines) and Ni, Xiandai Mianyixue, 26(4):265-268 (2006) (describing human-human hybridomas). Human hybridoma technology (Trioma technology) is also described in Vollmers and Brandlein, Histology and Histopathology, 20(3):927-937 (2005) and Vollmers and Brandlein, Methods and Findings in Experimental and Clinical Pharmacology, 27(3) :185-91 (2005).

Human antibodies may also be generated by isolating Fv clone variable domain sequences selected from human-derived phage display libraries. Such variable domain sequences may then be combined with a desired human constant domain. Techniques for selecting human antibodies from antibody libraries are described below.

5. Antibody variants

In some aspects, amino acid sequence variants of the bispecific anti-FcRH5/anti-CD3 antibodies described herein are contemplated. For example, it may be desirable to improve the binding affinity and/or other biological properties of the antibody. Amino acid sequence variants of an antibody may be prepared by introducing appropriate modifications into the nucleotide sequence encoding the antibody, or by peptide synthesis. Such modifications include, for example, deletions from, and/or insertions into and/or substitutions of residues within the amino acid sequences of the antibody. Any combination of deletion, insertion, and substitution can be made to arrive at the final construct, provided that the final construct possesses the desired characteristics, for example, antigen-binding. a. Substitution, insertion, and deletion variants

In certain embodiments, antibody variants having one or more amino acid substitutions are provided. Sites of interest for substitutional mutagenesis include the CDRs and FRs. Conservative substitutions are shown in Table 10 under the heading of “preferred substitutions.” More substantial changes are provided in Table 10 under the heading of “exemplary substitutions,” and as further described below in reference to amino acid side chain classes. Amino acid substitutions may be introduced into an antibody of interest and the products screened for a desired activity, for example, retained/improved antigen binding, decreased immunogenicity, or improved ADCC or CDC. Table 10. Exemplary and Preferred Amino Acid Substitutions

Amino acids may be grouped according to common side-chain properties:

(1 ) hydrophobic: Norleucine, Met, Ala, Vai, Leu, lie; (2) neutral hydrophilic: Cys, Ser, Thr, Asn, Gin;

(3) acidic: Asp, Glu;

(4) basic: His, Lys, Arg;

(5) residues that influence chain orientation: Gly, Pro;

(6) aromatic: Trp, Tyr, Phe. Non-conservative substitutions will entail exchanging a member of one of these classes for another class.

One type of substitutional variant involves substituting one or more hypervariable region residues of a parent antibody (e.g., a humanized or human antibody). Generally, the resulting variant(s) selected for further study will have modifications (e.g., improvements) in certain biological properties (e.g., increased affinity, reduced immunogenicity) relative to the parent antibody and/or will have substantially retained certain biological properties of the parent antibody. An exemplary substitutional variant is an affinity matured antibody, which may be conveniently generated, e.g., using phage display-based affinity maturation techniques such as those described herein. Briefly, one or more CDR residues are mutated and the variant antibodies displayed on phage and screened for a particular biological activity (e.g. binding affinity).

Alterations (e.g., substitutions) may be made in CDRs, e.g., to improve antibody affinity. Such alterations may be made in CDR “hotspots,” i.e. , residues encoded by codons that undergo mutation at high frequency during the somatic maturation process (see, e.g., Chowdhury, Methods Mol. Biol. 207:179-196 (2008)), and/or residues that contact an antigen, with the resulting variant VH or VL being tested for binding affinity. Affinity maturation by constructing and reselecting from secondary libraries has been described, e.g., in Hoogenboom et al. in Methods in Molecular Biology 178:1 -37 (O’Brien et al., ed., Human Press, Totowa, NJ, (2001 ).) In some embodiments of affinity maturation, diversity is introduced into the variable genes chosen for maturation by any of a variety of methods (e.g., error-prone PCR, chain shuffling, or oligonucleotide-directed mutagenesis). A secondary library is then created. The library is then screened to identify any antibody variants with the desired affinity. Another method to introduce diversity involves CDR-directed approaches, in which several CDR residues (e.g., 4-6 residues at a time) are randomized. CDR residues involved in antigen binding may be specifically identified, e.g., using alanine scanning mutagenesis or modeling. CDR-H3 and CDR-L3 in particular are often targeted.

In certain embodiments, substitutions, insertions, or deletions may occur within one or more CDRs so long as such alterations do not substantially reduce the ability of the antibody to bind antigen. For example, conservative alterations (e.g., conservative substitutions as provided herein) that do not substantially reduce binding affinity may be made in CDRs. Such alterations may, for example, be outside of antigen contacting residues in the CDRs. In certain embodiments of the variant VH and VL sequences provided above, each CDR either is unaltered, or contains no more than one, two or three amino acid substitutions.

A useful method for identification of residues or regions of an antibody that may be targeted for mutagenesis is called “alanine scanning mutagenesis” as described by Cunningham and Wells (1989) Science, 244:1081 -1085. In this method, a residue or group of target residues (e.g., charged residues such as arg, asp, his, lys, and glu) are identified and replaced by a neutral or negatively charged amino acid (e.g., alanine or polyalanine) to determine whether the interaction of the antibody with antigen is affected. Further substitutions may be introduced at the amino acid locations demonstrating functional sensitivity to the initial substitutions. Alternatively, or additionally, a crystal structure of an antigen-antibody complex to identify contact points between the antibody and antigen. Such contact residues and neighboring residues may be targeted or eliminated as candidates for substitution. Variants may be screened to determine whether they contain the desired properties. Amino acid sequence insertions include amino- and/or carboxyl-terminal fusions ranging in length from one residue to polypeptides containing a hundred or more residues, as well as intrasequence insertions of single or multiple amino acid residues. Examples of terminal insertions include an antibody with an N-terminal methionyl residue. Other insertional variants of the antibody molecule include the fusion to the N- or C-terminus of the antibody to an enzyme (e.g. for ADEPT) or a polypeptide which increases the serum half-life of the antibody. b. Glycosylation variants

In certain embodiments, the bispecific anti-FcRH5/anti-CD3 antibodies can be altered to increase or decrease the extent to which the antibody is glycosylated. Addition or deletion of glycosylation sites to the bispecific anti-FcRH5/anti-CD3 antibodies described herein may be conveniently accomplished by altering the amino acid sequence such that one or more glycosylation sites is created or removed.

Where the antibody comprises an Fc region, the carbohydrate attached thereto may be altered. Native antibodies produced by mammalian cells typically comprise a branched, biantennary oligosaccharide that is generally attached by an N-linkage to Asn297 of the CH2 domain of the Fc region. See, e.g., Wright et al. TIBTECH 15:26-32 (1997). The oligosaccharide may include various carbohydrates, e.g., mannose, N-acetyl glucosamine (GIcNAc), galactose, and sialic acid, as well as a fucose attached to a GIcNAc in the “stem” of the biantennary oligosaccharide structure. In some embodiments, modifications of the oligosaccharide in an antibody described herein may be made in order to create antibody variants with certain improved properties.

In one embodiment, bispecific anti-FcRH5/anti-CD3 antibody variants are provided having a carbohydrate structure that lacks fucose attached (directly or indirectly) to an Fc region. For example, the amount of fucose in such antibody may be from 1% to 80%, from 1% to 65%, from 5% to 65% or from 20% to 40%. The amount of fucose is determined by calculating the average amount of fucose within the sugar chain at Asn297, relative to the sum of all glycostructures attached to Asn 297 (e. g. complex, hybrid and high mannose structures) as measured by MALDI-TOF mass spectrometry, as described in WO 2008/077546, for example. Asn297 refers to the asparagine residue located at about position 297 in the Fc region (EU numbering of Fc region residues); however, Asn297 may also be located about ± 3 amino acids upstream or downstream of position 297, i.e., between positions 294 and 300, due to minor sequence variations in antibodies. Such fucosylation variants may have improved ADCC function. See, e.g., US Patent Publication Nos. US 2003/0157108 (Presta, L.); US 2004/0093621 (Kyowa Hakko Kogyo Co., Ltd). Examples of publications related to “defucosylated” or “fucose-deficient” antibody variants include: US 2003/0157108; WO 2000/61739; WO 2001/29246; US 2003/0115614; US 2002/0164328; US 2004/0093621 ; US 2004/0132140; US 2004/0110704; US 2004/0110282; US 2004/0109865; WO 2003/085119; WO 2003/084570; WO 2005/035586; WO 2005/035778; W02005/053742; W02002/031140; Okazaki et al. J. Mol. Biol. 336:1239-1249 (2004); Yamane-Ohnuki et al. Biotech. Bioeng. 87: 614 (2004). Examples of cell lines capable of producing defucosylated antibodies include Led 3 CHO cells deficient in protein fucosylation (Ripka et al. Arch. Biochem. Biophys. 249:533-545 (1986); US Pat Appl No US 2003/0157108 A1 , Presta, L; and WO 2004/056312 A1 , Adams et al., especially at Example 11 ), and knockout cell lines, such as alpha- 1 ,6-fucosyltransferase gene, FUT8, knockout CHO cells (see, e.g., Yamane-Ohnuki et al. Biotech. Bioeng. 87: 614 (2004); Kanda, Y. et al., Biotechnol. Bioeng., 94(4):680-688 (2006); and W02003/085107).

Bispecific anti-FcRH5/anti-CD3 antibody variants are further provided with bisected oligosaccharides, for example, in which a biantennary oligosaccharide attached to the Fc region of the antibody is bisected by GIcNAc. Such antibody variants may have reduced fucosylation and/or improved ADCC function. Examples of such antibody variants are described, e.g., in WO 2003/011878 (Jean-Mairet et al.); US Patent No. 6,602,684 (Umana et al.); and US 2005/0123546 (Umana et al.). Antibody variants with at least one galactose residue in the oligosaccharide attached to the Fc region are also provided. Such antibody variants may have improved CDC function. Such antibody variants are described, e.g., in WO 1997/30087 (Patel et al.); WO 1998/58964 (Raju, S.); and WO 1999/22764 (Raju, S.). c. Fc region variants

In certain embodiments, one or more amino acid modifications may be introduced into the Fc region of a bispecific anti-FcRH5/anti-CD3 antibody, thereby generating an Fc region variant (see e.g., US 2012/0251531 ). The Fc region variant may comprise a human Fc region sequence {e.g., a human IgG 1 , lgG2, lgG3 or lgG4 Fc region) comprising an amino acid modification {e.g., a substitution) at one or more amino acid positions.

In certain embodiments, the invention contemplates a bispecific anti-FcRH5/anti-CD3 antibody variant that possesses some but not all effector functions, which make it a desirable candidate for applications in which the half-life of the antibody in vivo is important, yet certain effector functions (such as complement and ADCC) are unnecessary or deleterious. In vitro and/or in vivo cytotoxicity assays can be conducted to confirm the reduction/depletion of CDC and/or ADCC activities. For example, Fc receptor (FcR) binding assays can be conducted to ensure that the antibody lacks FcyR binding (hence likely lacking ADCC activity), but retains FcRn binding ability. The primary cells for mediating ADCC, NK cells, express Fc(RI 11 only, whereas monocytes express Fc(RI, Fc(RI I and Fc(RII I . FcR expression on hematopoietic cells is summarized in Table 310 on page 464 of Ravetch and Kinet, Annu. Rev. Immunol. 9:457-492 (1991 ). Non-limiting examples of in vitro assays to assess ADCC activity of a molecule of interest is described in U.S. Patent No. 5,500,362 (see, e.g. Hellstrom, I. et al. Proc. Nat’ I Acad. Sci. USA 83:7059-7063 (1986)) and Hellstrom, I et al., Proc. Nat’l Acad. Sci. USA 82:1499-1502 (1985); 5,821 ,337 (see Bruggemann, M. et al., J. Exp. Med. 166:1351 -1361 (1987)). Alternatively, non-radioactive assays methods may be employed (see, for example, ACTI™ non-radioactive cytotoxicity assay for flow cytometry (CellTechnology, Inc. Mountain View, CA; and CytoTox 96® non-radioactive cytotoxicity assay (Promega, Madison, Wl). Useful effector cells for such assays include peripheral blood mononuclear cells (PBMC) and Natural Killer (NK) cells. Alternatively, or additionally, ADCC activity of the molecule of interest may be assessed in vivo, e.g., in an animal model such as that disclosed in Clynes et al. Proc. Nat’l Acad. Sci. USA 95:652-656 (1998). C1q binding assays may also be carried out to confirm that the antibody is unable to bind C1 q and hence lacks CDC activity. See, e.g., C1q and C3c binding ELISA in WO 2006/029879 and WO 2005/100402. To assess complement activation, a CDC assay may be performed (see, for example, Gazzano-Santoro et al. J. Immunol. Methods 202:163 (1996); Cragg, M.S. et al. Blood. 101 :1045-1052 (2003); and Cragg, M.S. and M.J. Glennie Blood. 103:2738-2743 (2004)). FcRn binding and in vivo clearance/half life determinations can also be performed using methods known in the art (see, e.g., Petkova, S.B. et al. Int’l. Immunol. 18(12):1759-1769 (2006)).

Antibodies with reduced effector function include those with substitution of one or more of Fc region residues 238, 265, 269, 270, 297, 327 and 329 (U.S. Patent Nos. 6,737,056 and 8,219,149). Such Fc mutants include Fc mutants with substitutions at two or more of amino acid positions 265, 269, 270, 297 and 327, including the so-called “DANA” Fc mutant with substitution of residues 265 and 297 to alanine (US Patent No. 7,332,581 and 8,219,149).

In certain embodiments, the proline at position 329 of a wild-type human Fc region in the antibody is substituted with glycine or arginine or an amino acid residue large enough to destroy the proline sandwich within the Fc/Fc.gamma. receptor interface that is formed between the proline 329 of the Fc and tryptophan residues Trp 87 and Trp 110 of FcgRIII (Sondermann et al. Nature. 406, 267- 273, 2000). In certain embodiments, the antibody comprises at least one further amino acid substitution. In one embodiment, the further amino acid substitution is S228P, E233P, L234A, L235A, L235E, N297A, N297D, or P331 S, and still in another embodiment the at least one further amino acid substitution is L234A and L235A of the human IgG 1 Fc region or S228P and L235E of the human lgG4 Fc region (see e.g., US 2012/0251531 ), and still in another embodiment the at least one further amino acid substitution is L234A and L235A and P329G of the human IgG 1 Fc region.

Certain antibody variants with improved or diminished binding to FcRs are described. (See, e.g., U.S. Patent No. 6,737,056; WO 2004/056312, and Shields et al., J. Biol. Chem. 9(2): 6591 -6604 (2001 ).)

In certain embodiments, an antibody variant comprises an Fc region with one or more amino acid substitutions which improve ADCC, e.g., substitutions at positions 298, 333, and/or 334 of the Fc region (EU numbering of residues).

In some embodiments, alterations are made in the Fc region that result in altered (/.e., either improved or diminished) C1q binding and/or Complement Dependent Cytotoxicity (CDC), e.g., as described in US Patent No. 6,194,551 , WO 99/51642, and Idusogie et al. J. Immunol. 164: 4178-4184 (2000).

Antibodies with increased half lives and improved binding to the neonatal Fc receptor (FcRn), which is responsible for the transfer of maternal IgGs to the fetus (Guyer et al., J. Immunol. 117:587 (1976) and Kim et al., J. Immunol. 24:249 (1994)), are described in US2005/0014934A1 (Hinton et al.). Those antibodies comprise an Fc region with one or more substitutions therein which improve binding of the Fc region to FcRn. Such Fc variants include those with substitutions at one or more of Fc region residues: 238, 256, 265, 272, 286, 303, 305, 307, 311 , 312, 317, 340, 356, 360, 362, 376, 378, 380, 382, 413, 424 or 434, e.g., substitution of Fc region residue 434 (US Patent No. 7,371 ,826).

See also Duncan & Winter, Nature 322:738-40 (1988); U.S. Patent No. 5,648,260; U.S. Patent No. 5,624,821 ; and WO 94/29351 concerning other examples of Fc region variants.

In some aspects, the bispecific anti-FcRH5/anti-CD3 antibody comprises an Fc region comprising an N297G mutation (EU numbering). In some aspects, the anti-FcRH5 arm of the bispecific anti-FcRH5/anti-CD3 antibody comprises a N297G mutation and/or the anti-CD3 arm of the bispecific anti-FcRH5/anti-CD3 antibody comprises an Fc region comprising an N297G mutation.

In some embodiments, the bispecific anti-FcRH5/anti-CD3 antibody comprising the N297G mutation comprises an anti-FcRH5 arm comprising a binding domain comprising the following six HVRs (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1 ; (b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 2; (c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 3; (d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 4; (e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and (f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 6; and an anti-CD3 arm comprising an N297G mutation. In some embodiments, the anti-CD3 arm comprising the N297G mutation comprises the following six HVRs: (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 9; (b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 10; (c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 11 ; (d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12; (e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 13; and (f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 14.

In some embodiments, the bispecific anti-FcRH5/anti-CD3 antibody comprising the N297G mutation comprises an anti-FcRH5 arm comprising a binding domain comprising (a) a VH domain comprising an amino acid sequence of SEQ ID NO: 7 and (b) a VL domain comprising an amino acid sequence of SEQ ID NO: 8, and an anti-CD3 arm comprising an N297G mutation. In some embodiments, the anti-CD3 arm comprising the N297G mutation comprises comprising (a) a VH domain comprising an amino acid sequence of SEQ ID NO: 15 and (b) a VL domain comprising an amino acid sequence of SEQ ID NO: 16.

In some embodiments, the bispecific anti-FcRH5/anti-CD3 antibody comprising the N297G mutation comprises one or more heavy chain constant domains, wherein the one or more heavy chain constant domains are selected from a first CH1 (CH1 1) domain, a first CH2 (CH2j) domain, a first CH3 (CH3y) domain, a second CH1 (CH1₂) domain, second CH2 (CH2₂) domain, and a second CH3 (CH3₂) domain. In some aspects, at least one of the one or more heavy chain constant domains is paired with another heavy chain constant domain. In some aspects, the CH3y and CH3₂ domains each comprise a protuberance or cavity, and wherein the protuberance or cavity in the CH3y domain is positionable in the cavity or protuberance, respectively, in the CH3₂ domain. In some aspects, the CH3y and CH3₂ domains meet at an interface between said protuberance and cavity. In some aspects, the CH2j and CH2₂ domains each comprise a protuberance or cavity, and wherein the protuberance or cavity in the CH2j domain is positionable in the cavity or protuberance, respectively, in the CH22 domain. In other instances, the CH2j and CH22 domains meet at an interface between said protuberance and cavity. In some aspects, the bispecific anti-FcRH5/anti-CD3 antibody is an IgGi antibody.

In some embodiments, the bispecific anti-FcRH5/anti-CD3 antibody comprising the N297G mutation comprises an anti-FcRH5 arm comprising a binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 7 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 8, and an anti-CD3 arm, wherein (a) the anti-FcRH5 arm comprises T366S, L368A, Y407V, and N297G amino acid substitution mutations (EU numbering) and (b) the anti-CD3 arm comprises T366W and N297G substitution mutations (EU numbering). In some embodiments, the anti-CD3 arm comprising the T366W and N297G mutations comprises comprising (a) a VH domain comprising an amino acid sequence of SEQ ID NO: 15 and (b) a VL domain comprising an amino acid sequence of SEQ ID NO: 16.

In other embodiments, the bispecific anti-FcRH5/anti-CD3 antibody comprising the N297G mutation comprises an anti-FcRH5 arm comprising a binding domain comprising (a) a VH domain comprising an amino acid sequence of SEQ ID NO: 7 and (b) a VL domain comprising an amino acid sequence of SEQ ID NO: 8, and an anti-CD3 arm, wherein (a) the anti-FcRH5 arm comprises T366W and N297G substitution mutations (EU numbering) and (b) the anti-CD3 arm comprises T366S, L368A, Y407V, and N297G mutations (EU numbering). In some embodiments, the anti-CD3 arm comprising the N297G mutation comprises comprising (a) a VH domain comprising an amino acid sequence of SEQ ID NO: 15 and (b) a VL domain comprising an amino acid sequence of SEQ ID NO: 16. d. Cysteine engineered antibody variants

In certain embodiments, it may be desirable to create cysteine engineered antibodies, e.g., “thioMAbs,” in which one or more residues of an antibody are substituted with cysteine residues. In particular embodiments, the substituted residues occur at accessible sites of the antibody. By substituting those residues with cysteine, reactive thiol groups are thereby positioned at accessible sites of the antibody and may be used to conjugate the antibody to other moieties, such as drug moieties or linker-drug moieties, to create an immunoconjugate, as described further herein. In certain embodiments, any one or more of the following residues may be substituted with cysteine: V205 (Kabat numbering) of the light chain; A118 (EU numbering) of the heavy chain; and S400 (EU numbering) of the heavy chain Fc region. Cysteine engineered antibodies may be generated as described, for example, in U.S. Patent No. 7,521 ,541 . e. Antibody derivatives

In certain embodiments, a bispecific anti-FcRH5/anti-CD3 antibody provided herein may be further modified to contain additional nonproteinaceous moieties that are known in the art and readily available. The moieties suitable for derivatization of the antibody include but are not limited to water soluble polymers. Non-limiting examples of water soluble polymers include, but are not limited to, polyethylene glycol (PEG), copolymers of ethylene glycol/propylene glycol, carboxymethylcellulose, dextran, polyvinyl alcohol, polyvinyl pyrrolidone, poly-1 , 3-dioxolane, poly-1 ,3, 6-trioxane, ethylene/maleic anhydride copolymer, polyaminoacids (either homopolymers or random copolymers), and dextran or poly(n-vinyl pyrrolidone)polyethylene glycol, propropylene glycol homopolymers, prolypropylene oxide/ethylene oxide co-polymers, polyoxyethylated polyols (e.g., glycerol), polyvinyl alcohol, and mixtures thereof. Polyethylene glycol propionaldehyde may have advantages in manufacturing due to its stability in water. The polymer may be of any molecular weight, and may be branched or unbranched. The number of polymers attached to the antibody may vary, and if more than one polymer are attached, they can be the same or different molecules. In general, the number and/or type of polymers used for derivatization can be determined based on considerations including, but not limited to, the particular properties or functions of the antibody to be improved, whether the antibody derivative will be used in a therapy under defined conditions, etc.

In another embodiment, conjugates of an antibody and nonproteinaceous moiety that may be selectively heated by exposure to radiation are provided. In one embodiment, the nonproteinaceous moiety is a carbon nanotube (Kam et al., Proc. Natl. Acad. Sci. USA 102: 11600-11605 (2005)). The radiation may be of any wavelength, and includes, but is not limited to, wavelengths that do not harm ordinary cells, but which heat the nonproteinaceous moiety to a temperature at which cells proximal to the antibody-nonproteinaceous moiety are killed.

6. Charged regions

In some aspects, the binding domain that binds FcRH5 or CD3 comprises a VH1 comprising a charged region (CRy) and a VL1 comprising a charged region (CR2), wherein the CRy in the VH1 forms a charge pair with the CR2 in the VL1 . In some aspects, the CRy comprises a basic amino acid residue and the CR2 comprises an acidic amino acid residue. In some aspects, the CRy comprises a Q39K substitution mutation (Kabat numbering). In some aspects, the CRy consists of the Q39K substitution mutation. In some aspects, the CR2 comprises a Q38E substitution mutation (Kabat numbering). In some aspects, the CR2 consists of the Q38E substitution mutation. In some aspects, the second binding domain that binds CD3 comprises a VH2 comprising a charged region (CR3) and a VL2 comprising a charged region (CR4), wherein the CR^in the VL2 forms a charge pair with the CR3 in the VH2. In some aspects, the CR4 comprises a basic amino acid residue and the CR3 comprises an acidic amino acid residue. In some aspects, the CR4 comprises a Q38K substitution mutation (Kabat numbering). In some aspects, the CR4 consists of the Q38K substitution mutation. In some aspects, the CR3 comprises a Q39E substitution mutation (Kabat numbering). In some aspects, the CR3 consists of the Q39E substitution mutation. In some aspects, the VL1 domain is linked to a light chain constant domain (CL1 ) domain and the VH1 is linked to a heavy chain constant domain (CH1 ), wherein the CL1 comprises a charged region (CR5) and the CH1 comprises a charged region (CRe), and wherein the CR5 in the CL1 forms a charge pair with the CRgin the CH1 y. In some aspects, the CR5 comprises a basic amino acid residue and the CRe comprises an acidic residue. In some aspects, the CR5 comprises a V133K substitution mutation (EU numbering). In some aspects, the CRs consists of the V133K substitution mutation. In some aspects, the CRs comprises a S183E substitution mutation (EU numbering). In some aspects, the CRs consists of the S183E substitution mutation.

In other aspects, the VL2 domain is linked to a CL domain (CL2) and the VH2 is linked to a CH1 domain (CH1₂), wherein the CL2 comprises a charged region (CR/) and the CH1₂ comprises a charged region (CRs), and wherein the CRs in the CH1₂ forms a charge pair with the CR/ in the CL2. In some aspects, the CRs comprises a basic amino acid residue and the CR/comprises an acidic amino acid residue. In some aspects, the CRs comprises a S183K substitution mutation (EU numbering). In some aspects, the CRs consists of the S183K substitution mutation. In some aspects, the CR/Comprises a V133E substitution mutation (EU numbering). In some aspects, the CR/ consists of the V133E substitution mutation.

In other aspects, the VL2 domain is linked to a CL domain (CL2) and the VH2 is linked to a CH1 domain (CH1₂), wherein (a) the CL2 comprises one or more mutations at amino acid residues F1 16, L135, S174, S176, and/or T178 (EU numbering) and (b) the CH1₂ comprises one or more mutations at amino acid residues A141 , F170, S181 , S183, and/or V185 (EU numbering). In some aspects, the CL2 comprises one or more of the following substitution mutations: F1 16A, L135V, S174A, S176F, and/or T 178V. In some aspects, the CL2 comprises the following substitution mutations: F1 16A, L135V, S174A, S176F, and T 178V. In some aspects, the CH1₂ comprises one or more of the following substitution mutations: A141 1, F170S, S181 M, S183A, and/or V185A. In some aspects, the CH1₂ comprises the following substitution mutations: A141 1, F170S, S181 M, S183A, and V185A.

In other aspects, the binding domain that binds FcRH5 or CD3 comprises a VH domain (VH1 ) comprising a charged region (CRy) and a VL domain (VL1 ) comprising a charged region (CR2), wherein the CR₂ in the VLy forms a charge pair with the CRy in the VH1 . In some aspects, the CR2 comprises a basic amino acid residue and the CRy comprises an acidic amino acid residue. In some aspects, the CR₂ comprises a Q38K substitution mutation (Kabat numbering). In some aspects, the CR₂ consists of the Q38K substitution mutation. In some aspects, the CRy comprises a Q39E substitution mutation (Kabat numbering). In some aspects, the CRy consists of the Q39E substitution mutation. In some aspects, the second binding domain that binds CD3 comprises a VH domain (VH2) comprising a charged region (CR3) and a VL domain (VL2) comprising a charged region (CR4), wherein the CR3 in the VH2 forms a charge pair with the CR4 in the VL2. In some aspects, the CR3 comprises a basic amino acid residue and the CR4 comprises an acidic amino acid residue. In some aspects, the CR3 comprises a Q39K substitution mutation (Kabat numbering). In some aspects, the CR3 consists of the Q39K substitution mutation. In some aspects, the CR4 comprises a Q38E substitution mutation (Kabat numbering). In some aspects, the CR4 consists of the Q38E substitution mutation. In some aspects, the VL1 domain is linked to a light chain constant domain (CL1 ) and the VH1 is linked to a first heavy chain constant domain (CH1 y), wherein the CL1 comprises a charged region (CRs) and the CH1 y comprises a charged region (CRs), and wherein the CRs in the CH1 y forms a charge pair with the CRs in the CL1 . In some aspects, the CRs comprises a basic amino acid residue and the CRs comprises an acidic amino acid residue. In some aspects, the CRg comprises a S183K substitution mutation (EU numbering). In some aspects, the CRe consists of the S183K substitution mutation. In some aspects, the CRs comprises a V133E substitution mutation (EU numbering). In some aspects, the CRs consists of the V133E substitution mutation.

In other aspects, the VL2 domain is linked to a CL domain (CL2) and the VH2 is linked to a CH1 domain (CH1₂), wherein the CL2 comprises a charged region (CR/) and the CH1₂ comprises a charged region (CRs), and wherein the CR/ in the CL2 forms a charged pair with the CRs in the CH1₂. In some aspects, the CR/ comprises a basic amino acid residue and the CRs comprises an acidic residue. In some aspects, the CR/ comprises a V133K substitution mutation (EU numbering). In some aspects, the CR/ consists of the V133K substitution mutation. In some aspects, the CRs comprises a S183E substitution mutation (EU numbering). In some aspects, the CRs consists of the S183E substitution mutation.

In other aspects, the VL2 domain is linked to a CL domain (CL2) and the VH2 is linked to a CH1 domain (CH1₂), wherein (a) the CL2 comprises one or more mutations at amino acid residues F1 16, L135, S174, S176, and/or T178 (EU numbering) and (b) the CH1₂ comprises one or more mutations at amino acid residues A141 , F170, S181 , S183, and/or V185 (EU numbering). In some aspects, the CL2 comprises one or more of the following substitution mutations: F1 16A, L135V, S174A, S176F, and/or T 178V. In some aspects, the CL2 comprises the following substitution mutations: F1 16A, L135V, S174A, S176F, and T 178V. In some aspects, the CH1₂ comprises one or more of the following substitution mutations: A141 1, F170S, S181 M, S183A, and/or V185A. In some aspects, the CH1₂ comprises the following substitution mutations: A141 1, F170S, S181 M, S183A, and V185A. In some aspects, the bispecific anti-FcRH5/anti-CD3 antibody comprises one or more heavy chain constant domains, wherein the one or more heavy chain constant domains are selected from a first CH2 domain (CH2y), a first CH3 domain (CH3y), a second CH2 domain (CH2₂), and a second CH3 domain (CH3₂). In some aspects, at least one of the one or more heavy chain constant domains is paired with another heavy chain constant domain. In some aspects, the CH3y and the CH3₂ each comprise a protuberance (Py) or a cavity (Cy), and wherein the Py or the Cy in the CH3y is positionable in the Cy or the Py, respectively, in the CH3₂. In some aspects, the CH3y and the CH3₂ meet at an interface between the Py and the Cy. In some aspects, the CH2y and the CH2₂ each comprise (P₂) or a cavity (C₂), and wherein the P₂ or the C₂ in the CH2 y is positionable in the C₂ or the P₂, respectively, in the CH2₂. In some aspects, the CH2y and the CH2₂ meet at an interface between the P₂ and the C₂.

A. Methods of administration

The methods may involve administering the bispecific anti-FcRH5/anti-CD3 antibody (and/or any additional therapeutic agent) by any suitable means, including parenteral, intrapulmonary, and intranasal, and, if desired for local treatment, intralesional administration. Parenteral infusions include intravenous, subcutaneous, intramuscular, intraarterial, and intraperitoneal administration routes. In some embodiments, the bispecific anti-FcRH5/anti-CD3 antibody is administered by intravenous infusion. In other instances, the bispecific anti-FcRH5/anti-CD3 antibody is administered subcutaneously.

In some instances, the bispecific anti-FcRH5/anti-CD3 antibody administered by intravenous injection exhibits a less toxic response (i.e. , fewer unwanted effects) in a patient than the same bispecific anti-FcRH5/anti-CD3 antibody administered by subcutaneous injection, or vice versa.

In some aspects, the bispecific anti-FcRH5/anti-CD3 antibody is administered intravenously over 4 hours (± 15 minutes), e.g., the first dose of the antibody is administered over 4 hours ± 15 minutes.

In some aspects, the first dose and the second dose of the antibody are administered intravenously with a median infusion time of less than four hours (e.g., less than three hours, less than two hours, or less than one hour) and further doses of the antibody are administered intravenously with a median infusion time of less than 120 minutes (e.g., less than 90 minutes, less than 60 minutes, or less than 30 minutes.

In some aspects, the first dose and the second dose of the antibody are administered intravenously with a median infusion time of less than three hours and further doses of the antibody are administered intravenously with a median infusion time of less than 90 minutes.

In some aspects, the first dose and the second dose of the antibody are administered intravenously with a median infusion time of less than three hours and further doses of the antibody are administered intravenously with a median infusion time of less than 60 minutes. In some aspects, the patient is hospitalized (e.g., hospitalized for 72 hours, 48 hours, 24 hours, or less than 24 hours) during one or more administrations of the anti-FcRH5/anti-CD3 antibody, e.g., hospitalized for the C1 D1 (cycle 1 , dose 1 ) or the C1 D1 and the C1 D2 (cycle 1 , dose 2). In some aspects, the patient is hospitalized for 72 hours following administration of the C1 D1 and the C1 D2. In some aspects, the patient is hospitalized for 24 hours following administration of the C1 D1 and the C1 D2. In some aspects, the patient is not hospitalized following the administration of any dose of the anti- FcRH5/anti-CD3 antibody.

For all the methods described herein, the bispecific anti-FcRH5/anti-CD3 antibody would be formulated, dosed, and administered in a fashion consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners. The bispecific anti-FcRH5/anti-CD3 antibody need not be, but is optionally formulated with, one or more agents currently used to prevent or treat the disorder in question. The effective amount of such other agents depends on the amount of the bispecific anti-FcRH5/anti-CD3 antibody present in the formulation, the type of disorder or treatment, and other factors discussed above. The bispecific anti-FcRH5/anti-CD3 antibody may be suitably administered to the patient over a series of treatments. B. Recombinant methods and compositions

In any one of the above aspects, an anti-FcRH5/anti-CD3 bispecific antibody provided herein is a multispecific antibody, for example, a bispecific antibody. Multispecific antibodies are antibodies (e.g., monoclonal antibodies) that have binding specificities for at least two different sites, e.g., antibodies having binding specificities for an immune effector cell and for a cell surface antigen (e.g., a tumor antigen, e.g., FcRH5) on a target cell other than an immune effector cell. In some aspects, one of the binding specificities is for FcRH5 and the other is for CD3.

In some aspects, the cell surface antigen may be expressed in low copy number on the target cell. For example, in some aspects, the cell surface antigen is expressed or present at less than 35,000 copies per target cell. In some embodiments, the low copy number cell surface antigen is present between 100 and 35,000 copies per target cell; between 100 and 30,000 copies per target cell; between 100 and 25,000 copies per target cell; between 100 and 20,000 copies per target cell; between 100 and 15,000 copies per target cell; between 100 and 10,000 copies per target cell; between 100 and 5,000 copies per target cell; between 100 and 2,000 copies per target cell; between 100 and 1 ,000 copies per target cell; or between 100 and 500 copies per target cell. Copy number of the cell surface antigen can be determined, for example, using a standard Scatchard plot.

In some embodiments, a bispecific antibody may be used to localize a cytotoxic agent to a cell that expresses a tumor antigen, e.g., FcRH5. Bispecific antibodies may be prepared as full-length antibodies or antibody fragments.

Techniques for making multispecific antibodies include, but are not limited to, recombinant coexpression of two immunoglobulin heavy chain-light chain pairs having different specificities (see Milstein and Cuello, Nature 305: 537 (1983)), WO 93/08829, and Traunecker et al., EMBO J. 10: 3655 (1991 )), and “knob-in-hole” (KnH) engineering (see, e.g., U.S. Patent No. 5,731 ,168). “Knob-in- hole” engineering of multispecific antibodies may be utilized to generate a first arm containing a knob and a second arm containing the hole into which the knob of the first arm may bind. The knob of the multispecific antibodies described herein may be an anti-CD3 arm in one embodiment. Alternatively, the knob of the multispecific antibodies described herein may be an anti-target/antigen arm in one embodiment. The hole of the multispecific antibodies described herein may be an anti-CD3 arm in one embodiment. Alternatively, the hole of the multispecific antibodies described herein may be an anti-target/antigen arm in one embodiment.

Multispecific antibodies may also be engineered using immunoglobulin crossover (also known as Fab domain exchange or CrossMab format) technology (see, e.g., W02009/080253; Schaefer et al., Proc. Natl. Acad. Sci. USA, 108:1 1 187-1 1 192 (201 1 )). Multi-specific antibodies may also be made by engineering electrostatic steering effects for making antibody Fc-heterodimeric molecules (WO 2009/089004A1 ); cross-linking two or more antibodies or fragments (see, e.g., US Patent No. 4,676,980, and Brennan et al., Science, 229: 81 (1985)); using leucine zippers to produce bi-specific antibodies (see, e.g., Kostelny et al., J. Immunol., 148(5):1547-1553 (1992)); using “diabody” technology for making bispecific antibody fragments (see, e.g., Hollinger et al., Proc. Natl. Acad. Sci. USA, 90:6444-6448 (1993)); and using single-chain Fv (sFv) dimers (see, e.g. Gruber et al., J. Immunol., 152:5368 (1994)); and preparing trispecific antibodies as described, e.g., in Tutt et al. J. Immunol. 147: 60 (1991 ).

Engineered antibodies with three or more functional antigen binding sites, including “Octopus antibodies,” are also included herein (see, e.g. US 2006/0025576A1 ).

The antibodies, or antibody fragments thereof, may also include a “Dual Acting FAb” or “DAF” comprising an antigen binding site that binds to CD3 as well as another, different antigen (e.g., a second biological molecule) (see, e.g., US 2008/0069820).

Bispecific anti-FcRH5/anti-CD3 antibodies described herein may be produced using recombinant methods and compositions, for example, as described in U.S. Patent No. 4,816,567. In one embodiment, an isolated nucleic acid encoding an anti-FcRH5/anti-CD3 bispecific antibody described herein is provided. Such nucleic acid may encode an amino acid sequence comprising the VL and/or an amino acid sequence comprising the VH of the antibody (e.g., the light and/or heavy chains of the antibody). In a further embodiment, one or more vectors (e.g., expression vectors) comprising such a nucleic acid are provided. In a further embodiment, a host cell comprising such a nucleic acid is provided. In one such embodiment, a host cell comprises (e.g., has been transformed with): (1 ) a vector comprising a nucleic acid that encodes an amino acid sequence comprising the VL of the antibody and an amino acid sequence comprising the VH of the antibody, or (2) a first vector comprising a nucleic acid that encodes an amino acid sequence comprising the VL of the antibody and a second vector comprising a nucleic acid that encodes an amino acid sequence comprising the VH of the antibody. In one embodiment, the host cell is eukaryotic, e.g. a Chinese Hamster Ovary (CHO) cell or lymphoid cell (e.g., Y0, NS0, Sp20 cell). In one embodiment, a method of making a bispecific anti-FcRH5/anti-CD3 antibody is provided, wherein the method comprises culturing a host cell comprising a nucleic acid encoding the antibody, as provided above, under conditions suitable for expression of the antibody, and optionally recovering the antibody from the host cell (or host cell culture medium).

For recombinant production of a bispecific anti-FcRH5/anti-CD3 antibody, a nucleic acid encoding an antibody, e.g., as described above, is isolated and inserted into one or more vectors for further cloning and/or expression in a host cell. Such nucleic acid may be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to genes encoding the heavy and light chains of the antibody).

1. Two-cell methods for manufacturing bispecific antibodies

In some aspects, an antibody described herein (e.g., a bispecific anti-FcRH5/anti-CD3 antibody) is manufactured using a method comprising two host cell lines. In some aspects, a first arm of the antibody (e.g., a first arm comprising a hole region) is produced in a first host cell line, and a second arm of the antibody (e.g., a second arm comprising a knob region) is produced in a second host cell line. The arms of the antibody are purified from the host cell lines and assembled in vitro. 2. One-cell methods for manufacturing bispecific antibodies

In some aspects, an antibody described herein (e.g., a bispecific anti-FcRH5/anti-CD3 antibody) is manufactured using a method comprising a single host cell line. In some aspects, a first arm of the antibody (e.g., a first arm comprising a hole region) and a second arm of the antibody (e.g., a second arm comprising a knob region) are produced in and purified from a single host cell line. Preferably, the first arm and the second arm are expressed at comparable levels in the host cell, e.g., are both expressed at a high level in the host cell. Similar levels of expression increase the likelihood of efficient TDB production and decrease the likelihood of light chain (LC) mispairing of TDB components. The first arm and second arm of the antibody may each further comprise amino acid substitution mutations introducing charge pairs, as described herein. The charge pairs promote the pairing of heavy and light chain cognate pairs of each arm of the bispecific antibody, thereby minimizing mispairing.

3. Host cells

Suitable host cells for cloning or expression of antibody-encoding vectors include prokaryotic or eukaryotic cells described herein. For example, antibodies may be produced in bacteria, in particular when glycosylation and Fc effector function are not needed. For expression of antibody fragments and polypeptides in bacteria, see, e.g., U.S. Patent Nos. 5,648,237, 5,789,199, and 5,840,523. (See also Charlton, Methods in Molecular Biology, Vol. 248 (B.K.C. Lo, ed., Humana Press, Totowa, NJ, 2003), pp. 245-254, describing expression of antibody fragments in E. coli.) After expression, the antibody may be isolated from the bacterial cell paste in a soluble fraction and can be further purified.

In addition to prokaryotes, eukaryotic microbes such as filamentous fungi or yeast are suitable cloning or expression hosts for antibody-encoding vectors, including fungi and yeast strains whose glycosylation pathways have been “humanized,” resulting in the production of an antibody with a partially or fully human glycosylation pattern. See Gerngross, Nat. Biotech. 22:1409-1414 (2004), and Li et al., Nat. Biotech. 24:210-215 (2006).

Suitable host cells for the expression of glycosylated antibody are also derived from multicellular organisms (invertebrates and vertebrates). Examples of invertebrate cells include plant and insect cells. Numerous baculoviral strains have been identified which may be used in conjunction with insect cells, particularly for transfection of Spodoptera frugiperda cells.

Plant cell cultures can also be utilized as hosts. See, e.g., US Patent Nos. 5,959,177, 6,040,498, 6,420,548, 7,125,978, and 6,417,429 (describing PLANTIBODIES™ technology for producing antibodies in transgenic plants).

Vertebrate cells may also be used as hosts. For example, mammalian cell lines that are adapted to grow in suspension may be useful. Other examples of useful mammalian host cell lines are monkey kidney CV1 line transformed by SV40 (COS-7); human embryonic kidney line (293 or 293 cells as described, e.g., in Graham et al., J. Gen Virol. 36:59 (1977)); baby hamster kidney cells (BHK); mouse sertoli cells (TM4 cells as described, e.g., in Mather, Biol. Reprod. 23:243-251 (1980)); monkey kidney cells (CV1 ); African green monkey kidney cells (VERO-76); human cervical carcinoma cells (HELA); canine kidney cells (MDCK; buffalo rat liver cells (BRL 3A); human lung cells (W138); human liver cells (Hep G2); mouse mammary tumor (MMT 060562); TRI cells, as described, e.g., in Mather et al., Annals N. Y. Acad. Sci. 383:44-68 (1982); MRC 5 cells; and FS4 cells. Other useful mammalian host cell lines include Chinese hamster ovary (CHO) cells, including DHFR- CHO cells (Urlaub et al., Proc. Natl. Acad. Sci. USA 77:4216 (1980)); and myeloma cell lines such as Y0, NSO and Sp2/0. For a review of certain mammalian host cell lines suitable for antibody production, see, e.g., Yazaki and Wu, Methods in Molecular Biology, Vol. 248 (B.K.C. Lo, ed., Humana Press, Totowa, NJ), pp. 255-268 (2003).

C. Immunoconjugates

The invention also provides immunoconjugates comprising a bispecific anti-FcRH5/anti-CD3 antibody herein conjugated to one or more cytotoxic agents, such as chemotherapeutic agents or drugs, growth inhibitory agents, toxins (e.g., protein toxins, enzymatically active toxins of bacterial, fungal, plant, or animal origin, or fragments thereof), or radioactive isotopes.

In one embodiment, an immunoconjugate is an antibody-drug conjugate (ADC) in which an antibody is conjugated to one or more drugs, including but not limited to a maytansinoid (see U.S. Patent Nos. 5,208,020, 5,416,064 and European Patent EP 0 425 235 B1 ); an auristatin such as monomethylauristatin drug moieties DE and DF (MMAE and MMAF) (see U.S. Patent Nos. 5,635,483 and 5,780,588, and 7,498,298); a dolastatin; a calicheamicin or derivative thereof (see U.S. Patent Nos. 5,712,374, 5,714,586, 5,739,1 16, 5,767,285, 5,770,701 , 5,770,710, 5,773,001 , and 5,877,296; Hinman et al., Cancer Res. 53:3336-3342 (1993); and Lode et al., Cancer Res. 58:2925-2928 (1998)); an anthracycline such as daunomycin or doxorubicin (see Kratz et al., Current Med. Chem. 13:477-523 (2006); Jeffrey et al., Bioorganic & Med. Chem. Letters 16:358-362 (2006); Torgov et al., Bioconj. Chem. 16:717-721 (2005); Nagy et al., Proc. Natl. Acad. Sci. USA 97:829-834 (2000); Dubowchik et al., Bioorg. & Med. Chem. Letters 12:1529-1532 (2002); King et al., J. Med. Chem. 45:4336-4343 (2002); and U.S. Patent No. 6,630,579); methotrexate; vindesine; a taxane such as docetaxel, paclitaxel, larotaxel, tesetaxel, and ortataxel; a trichothecene; and CC1065.

In another embodiment, an immunoconjugate comprises a bispecific anti-FcRH5/anti-CD3 antibody as described herein conjugated to an enzymatically active toxin or fragment thereof, including but not limited to diphtheria A chain, nonbinding active fragments of diphtheria toxin, exotoxin A chain (from Pseudomonas aeruginosa), ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin, Aleurites fordii proteins, dianthin proteins, Phytolaca americana proteins (PAPI, PAPII, and PAP-S), momordica charantia inhibitor, curcin, crotin, sapaonaria officinalis inhibitor, gelonin, mitogellin, restrictocin, phenomycin, enomycin, and the tricothecenes.

In another embodiment, an immunoconjugate comprises a bispecific anti-FcRH5/anti-CD3 antibody described herein conjugated to a radioactive atom to form a radioconjugate. A variety of radioactive isotopes are available for the production of radioconjugates. Examples include At²¹¹ , I¹³¹ , I¹²⁵, Y⁹⁰, Re¹⁸⁶, Re¹⁸⁸, Sm¹⁵³, Bi²¹², P³², Pb²¹² and radioactive isotopes of Lu. When the radioconjugate is used for detection, it may comprise a radioactive atom for scintigraphic studies, for example tc99m or 1123, or a spin label for nuclear magnetic resonance (NMR) imaging (also known as magnetic resonance imaging, mri), such as iodine-123 again, iodine-131 , indium-111 , fluorine-19, carbon-13, nitrogen-15, oxygen-17, gadolinium, manganese or iron.

Conjugates of an antibody and cytotoxic agent may be made using a variety of bifunctional protein coupling agents such as N-succinimidyl-3-(2-pyridyldith io) propionate (SPDP), succinimidyl-4- (N-maleimidomethyl) cyclohexane-1 -carboxylate (SMCC), iminothiolane (IT), bifunctional derivatives of imidoesters (such as dimethyl adipimidate HCI), active esters (such as disuccinimidyl suberate), aldehydes (such as glutaraldehyde), bis-azido compounds (such as bis (p-azidobenzoyl) hexanediamine), bis-diazonium derivatives (such as bis-(p-diazoniumbenzoyl)-ethylenediamine), diisocyanates (such as toluene 2,6-diisocyanate), and bis-active fluorine compounds (such as 1 ,5- difluoro-2,4-dinitrobenzene). For example, a ricin immunotoxin can be prepared as described in Vitetta et al., Science 238:1098 (1987). Carbon-14-labeled 1 -isothiocyanatobenzyl-3- methyldiethylene triaminepentaacetic acid (MX-DTPA) is an exemplary chelating agent for conjugation of radionucleotide to the antibody. See WO94/11026. The linker may be a “cleavable linker” facilitating release of a cytotoxic drug in the cell. For example, an acid-labile linker, peptidasesensitive linker, photolabile linker, dimethyl linker or disulfide-containing linker (Chari et al., Cancer Res. 52:127-131 (1992); U.S. Patent No. 5,208,020) may be used.

The immunuoconjugates or ADCs herein expressly contemplate, but are not limited to such conjugates prepared with cross-linker reagents including, but not limited to, BMPS, EMCS, GMBS, HBVS, LC-SMCC, MBS, MPBH, SBAP, SIA, SIAB, SMCC, SMPB, SMPH, sulfo-EMCS, sulfo-GMBS, sulfo-KMUS, sulfo-MBS, sulfo-SIAB, sulfo-SMCC, and sulfo-SMPB, and SVSB (succinimidyl-(4- vinylsulfone)benzoate) which are commercially available (e.g., from Pierce Biotechnology, Inc., Rockford, IL., U.S.A).

D. Pharmaceutical compositions and formulations

Pharmaceutical compositions and formulations of the anti-FcRH5/anti-CD3 bispecific antibodies can be prepared by mixing such antibodies having the desired degree of purity with one or more optional pharmaceutically acceptable carriers {Remington’s Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)), in the form of lyophilized formulations or aqueous solutions. Pharmaceutically acceptable carriers are generally nontoxic to recipients at the dosages and concentrations employed, and include, but are not limited to: buffers such as L-Histidine/glacial acetic acid (e.g., at pH 5.8), phosphate, citrate, and other organic acids; tonicity agents, such as sucrose; stabilizers, such as L-methionine; antioxidants including N-acetyl-DL-tryptophan, ascorbic acid, and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m- cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g. Zn-protein complexes); and/or non-ionic surfactants such as polysorbate 20 or polyethylene glycol (PEG). Exemplary pharmaceutically acceptable carriers herein further include insterstitial drug dispersion agents such as soluble neutral-active hyaluronidase glycoproteins (sHASEGP), for example, human soluble PH-20 hyaluronidase glycoproteins, such as rHuPH20 (HYLENEX®, Baxter International, Inc.). Certain exemplary sHASEGPs and methods of use, including rHuPH20, are described in US Patent Publication Nos. 2005/0260186 and 2006/0104968. In one aspect, a sHASEGP is combined with one or more additional glycosaminoglycanases such as chondroitinases.

Exemplary lyophilized antibody formulations are described in US Patent No. 6,267,958. Aqueous antibody formulations include those described in US Patent No. 6,171 ,586 and W02006/044908, the latter formulations including a histidine-acetate buffer.

The formulation herein may also contain more than one active ingredients as necessary for the particular indication being treated, preferably those with complementary activities that do not adversely affect each other. For example, it may be desirable to further provide an additional therapeutic agent (e.g., a chemotherapeutic agent, a cytotoxic agent, a growth inhibitory agent, and/or an anti-hormonal agent, such as those recited herein above). Such active ingredients are suitably present in combination in amounts that are effective for the purpose intended.

Active ingredients may be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions. Such techniques are disclosed in Remington’s Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980).

Sustained-release preparations may be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, for example, films, or microcapsules.

The formulations to be used for in vivo administration are generally sterile. Sterility may be readily accomplished, e.g., by filtration through sterile filtration membranes.

E. Dosing regimens

Single step-up dosing regimens

In some aspects, the methods described herein comprise administering to the subject having a multiple myeloma (MM) a bispecific antibody that binds to FcRH5 and CD3 in a single step-up dosing regimen.

In some aspects, the invention provides a method of treating a subject having a MM (e.g., a relapsed or refractory (R/R) MM) comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 in a dosing regimen comprising at least a first dosing cycle, wherein the first dosing cycle comprises a first dose (C1 D1 ) and a second dose (C1 D2) of the bispecific antibody, wherein the C1 D1 is between about 0.05 mg to about 180 mg (e.g., between about 0.1 mg to about 160 mg, between about 0.5 mg to about 140 mg, between about 1 mg to about 120 mg, between about 1 .5 mg to about 100 mg, between about 2.0 mg to about 80 mg, between about 2.5 mg to about 50 mg, between about 3.0 mg to about 25 mg, between about 3.0 mg to about 15 mg, between about 3.0 mg to about 10 mg, or between about 3.0 mg to about 5 mg) and the C1 D2 is between about 0.15 mg to about 1000 mg (e.g., between about 0.5 mg to about 800 mg, between about 1 mg to about 700 mg, between about 5 mg to about 500 mg, between about 10 mg to about 400 mg, between about 25 mg to about 300 mg, between about 40 mg to about 200 mg, between about 50 mg to about 100 mg, between about 75 mg to about 100 mg, or between about 85 mg to about 100 mg) and the C1 D2 is between about 0.15 mg to about 1000 mg (e.g., between about 0.5 mg to about 800 mg, between about 1 mg to about 700 mg, between about 5 mg to about 500 mg, between about 10 mg to about 400 mg, between about 25 mg to about 300 mg, between about 50 mg to about 250 mg, between about 100 mg to about 225 mg, or between about 150 mg to about 200 mg).

In some aspects, the method of treating a subject having a MM comprises administering to the subject a bispecific antibody that binds to FcRH5 and CD3 in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein (a) the first dosing cycle comprises a first dose (C1 D1 ; cycle 1 , dose 1 ) and a second dose (C1 D2; cycle 1 , dose, 2) of the bispecific antibody, wherein the C1 D1 is less than the C1 D2, and wherein the C1 D1 is between about 0.05 mg to about 180 mg (e.g., between about 0.1 mg to about 160 mg, between about 0.5 mg to about 140 mg, between about 1 mg to about 120 mg, between about 1 .5 mg to about 100 mg, between about 2.0 mg to about 80 mg, between about 2.5 mg to about 50 mg, between about 3.0 mg to about 25 mg, between about 3.0 mg to about 15 mg, between about 3.0 mg to about 10 mg, or between about 3.0 mg to about 5 mg) and the C1 D2 is between about 0.15 mg to about 1000 mg (e.g., between about 0.5 mg to about 800 mg, between about 1 mg to about 700 mg, between about 5 mg to about 500 mg, between about 10 mg to about 400 mg, between about 25 mg to about 300 mg, between about 40 mg to about 200 mg, between about 50 mg to about 100 mg, between about 75 mg to about 100 mg, or between about 85 mg to about 100 mg); and (b) the second dosing cycle comprises a single dose (C2D1 ; cycle 2, dose 1 ) of the bispecific antibody, wherein the C2D1 is equal to or greater than the C1 D2 and is between about 0.15 mg to about 1000 mg (e.g., between about 0.5 mg to about 800 mg, between about 1 mg to about 700 mg, between about 5 mg to about 500 mg, between about 10 mg to about 400 mg, between about 25 mg to about 300 mg, between about 40 mg to about 200 mg, between about 50 mg to about 100 mg, between about 75 mg to about 100 mg, or between about 85 mg to about 100 mg).

In some aspects, (a) the C1 D1 is between about 0.5 mg to about 19.9 mg (e.g., between about 1 mg to about 18 mg, between about 2 mg to about 15 mg, between about 3 mg to about 10 mg, between about 3.3 mg to about 6 mg, or between about 3.4 mg to about 4 mg, e.g., about 3 mg, 3.2 mg, 3.4 mg, 3.6 mg, 3.8 mg, 4 mg, 4.2 mg, 4.4 mg, 4.6 mg, 4.8 mg, 5 mg, 5.2 mg, 5.6 mg, 5.8 mg, 6 mg, 6.2 mg, 6.4 mg, 6.6 mg, 6.8 mg, 7 mg, 7.2 mg, 7.4 mg, 7.6 mg, 7.8 mg, 8 mg, 8.2 mg, 8.4 mg,

8.6 mg, 8.8 mg, 9 mg, 9.2 mg, 9.4 mg, 9.6 mg, 9.8 mg, 10 mg, 10.2 mg, 10.4 mg, 10.6 mg, 10.8 mg,

1 1 mg, 1 1 .2 mg, 1 1 .4 mg, 1 1 .6 mg, 1 1 .8 mg, 12 mg, 12.2 mg, 12.4 mg, 12.6 mg, 12.8 mg, 13 mg, 13.2 mg, 13.4 mg, 13.6 mg, 13.8 mg, 14 mg, 14.2 mg, 14.4 mg, 14.6 mg, 14.8 mg, 15 mg, 15.2 mg,

15.4 mg, 15.6 mg, 15.8 mg, 16 mg, 16.2 mg, 16.4 mg, 16.6 mg, 16.8 mg, 17 mg, 18.2 mg, 18.4 mg,

18.6 mg, 18.8 mg, 19 mg, 19.2 mg, 19.4 mg, 19.6 mg, or 19.8 mg), and (b) the C1 D2 is between about 20 mg to about 600 mg (e.g., between about 30 mg to 500 mg, 40 mg to 400 mg, 60 mg to 350 mg, 80 mg to 300 mg, 100 mg to 200 mg, or 140 mg to 180 mg, e.g., about 20, 40, 60, 80, 100, 120, 140, 160, 180, 200, 220, 240, 260, 280, 300, 320, 340, 360, 380, 400, 420, 440, 460, 480, 500, 520, 540, 560, 580, or 600 mg).

In some aspects, the C1 D1 is between about 1 .2 mg to about 10.8 mg and the C1 D2 is between about 80 mg to about 300 mg. In some aspects, the C1 D1 is about 3.6 mg and the C1 D2 is about 198 mg. In some aspects, the C1 D1 is between 1 .2 mg to 10.8 mg and the C1 D2 is between 80 mg to 300 mg. In some aspects, the C1 D1 is 3.6 mg and the C1 D2 is 198 mg.

In some instances, the methods described above may include a first dosing cycle of three weeks or 21 days. In some instances, the methods may include administering to the subject the C1 D1 and the C1 D2 on or about Days 1 and 8, respectively, of the first dosing cycle.

Double step-up dosing regimens

In other aspects, the methods described herein comprise administering to the subject having a multiple myeloma (MM) a bispecific antibody that binds to FcRH5 and CD3 in a double step-up dosing regimen.

In some aspects, the method comprises administering to the subject a bispecific antibody that binds to FcRH5 and CD3 in a dosing regimen comprising at least a first dosing cycle, wherein the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of the bispecific antibody, wherein the C1 D1 is between about 0.2 mg to about 0.4 mg (e.g., is about 0.20 mg, 0.21 mg, 0.22 mg, 0.23 mg, 0.24 mg, 0.25 mg, 0.26 mg, 0.27 mg, 0.28 mg, 0.29 mg, 0.30 mg, 0.31 mg, 0.32 mg, 0.33 mg, 0.34 mg, 0.35 mg, 0.36 mg, 0.37 mg, 0.38 mg, 0.39mg, or 0.40 mg); the C1 D2 is greater than the C1 D1 , and the C1 D3 is greater than the C1 D2. In some aspects, the C1 D1 is about 0.3 mg.

In some aspects, the C1 D1 is between 0.2 mg to and 0.4 mg (e.g., is 0.20 mg, 0.21 mg, 0.22 mg, 0.23 mg, 0.24 mg, 0.25 mg, 0.26 mg, 0.27 mg, 0.28 mg, 0.29 mg, 0.30 mg, 0.31 mg, 0.32 mg, 0.33 mg, 0.34 mg, 0.35 mg, 0.36 mg, 0.37 mg, 0.38 mg, 0.39mg, or 0.40 mg). In some aspects, the C1 D1 is 0.3 mg.

In some aspects, the method comprises administering to the subject a bispecific antibody that binds to FcRH5 and CD3 in a dosing regimen comprising at least a first dosing cycle, wherein the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of the bispecific antibody, wherein the C1 D1 is between about 0.01 mg to about 2.9 mg, the C1 D2 is between about 3 mg to about 19.9 mg, and the C1 D3 is between about 20 mg to about 600 mg. In some aspects, the method comprises administering to the subject a bispecific antibody that binds to FcRH5 and CD3 in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein (a) the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of the bispecific antibody, wherein the C1 D1 and the C1 D2 are each less than the C1 D3, and wherein the C1 D1 is between about 0.01 mg to about 2.9 mg, the C1 D2 is between about 3 mg to about 19.9 mg, and the C1 D3 is between about 20 mg to about 600 mg; and (b) the second dosing cycle comprises a single dose (C2D1 ) of the bispecific antibody, wherein the C2D1 is equal to or greater than the C1 D3 and is between about 20 mg to about 600 mg.

In some aspects, the C1 D1 is between about 0.05 mg to about 2.5 mg, about 0.1 mg to about 2 mg, about 0.2 mg to about 1 mg, or about 0.2 mg to about 0.4 mg (e.g., about 0.01 mg, 0.05 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.9 mg, 1 mg, 1 .1 mg, 1 .2 mg, 1 .3 mg, 1 .4 mg, 1 .5 mg, 1 .6 mg, 1 .7 mg, 1 .8 mg, 1 .9 mg, 2 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, or 2.9 mg). In some aspects, the C1 D1 is about 0.3 mg.

In some aspects, the C1 D1 is between 0.05 mg to 2.5 mg, 0.1 mg to 2 mg, 0.2 mg to 1 mg, or 0.2 mg to 0.4 mg (e.g., 0.01 mg, 0.05 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.9 mg, 1 mg, 1 .1 mg, 1 .2 mg, 1 .3 mg, 1 .4 mg, 1 .5 mg, 1 .6 mg, 1 .7 mg, 1 .8 mg, 1 .9 mg, 2 mg, 2.1 mg,

2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, or 2.9 mg). In some aspects, the C1 D1 is 0.3 mg.

In some aspects, the C1 D2 is between about 3 mg to about 19.9 mg (e.g., between about 3 mg to about 18 mg, between about 3.1 mg to about 15 mg, between about 3.2 mg to about 10 mg, between about 3.3 mg to about 6 mg, or between about 3.4 mg to about 4 mg, e.g., about 3 mg, 3.2 mg, 3.4 mg, 3.6 mg, 3.8 mg, 4 mg, 4.2 mg, 4.4 mg, 4.6 mg, 4.8 mg, 5 mg, 5.2 mg, 5.6 mg, 5.8 mg, 6 mg, 6.2 mg, 6.4 mg, 6.6 mg, 6.8 mg, 7 mg, 7.2 mg, 7.4 mg, 7.6 mg, 7.8 mg, 8 mg, 8.2 mg, 8.4 mg, 8.6 mg, 8.8 mg, 9 mg, 9.2 mg, 9.4 mg, 9.6 mg, 9.8 mg, 10 mg, 10.2 mg, 10.4 mg, 10.6 mg, 10.8 mg, 1 1 mg, 1 1 .2 mg, 1 1 .4 mg, 1 1 .6 mg, 1 1 .8 mg, 12 mg, 12.2 mg, 12.4 mg, 12.6 mg, 12.8 mg, 13 mg, 13.2 mg, 13.4 mg, 13.6 mg, 13.8 mg, 14 mg, 14.2 mg, 14.4 mg, 14.6 mg, 14.8 mg, 15 mg, 15.2 mg, 15.4 mg, 15.6 mg, 15.8 mg, 16 mg, 16.2 mg, 16.4 mg, 16.6 mg, 16.8 mg, 17 mg, 18.2 mg, 18.4 mg, 18.6 mg, 18.8 mg, 19 mg, 19.2 mg, 19.4 mg, 19.6 mg, or 19.8 mg). In some aspects, the C1 D2 is between about 3.2 mg to about 10 mg. In some aspects, the C1 D2 is about 3.6 mg.

In some aspects, the C1 D2 is between 3 mg to 19.9 mg (e.g., between 3 mg to 18 mg, between 3.1 mg to 15 mg, between 3.2 mg to 10 mg, between 3.3 mg to 6 mg, or between 3.4 mg to 4 mg, e.g., 3 mg, 3.2 mg, 3.4 mg, 3.6 mg, 3.8 mg, 4 mg, 4.2 mg, 4.4 mg, 4.6 mg, 4.8 mg, 5 mg, 5.2 mg, 5.6 mg, 5.8 mg, 6 mg, 6.2 mg, 6.4 mg, 6.6 mg, 6.8 mg, 7 mg, 7.2 mg, 7.4 mg, 7.6 mg, 7.8 mg, 8 mg, 8.2 mg, 8.4 mg, 8.6 mg, 8.8 mg, 9 mg, 9.2 mg, 9.4 mg, 9.6 mg, 9.8 mg, 10 mg, 10.2 mg, 10.4 mg, 10.6 mg, 10.8 mg, 1 1 mg, 1 1 .2 mg, 1 1 .4 mg, 1 1 .6 mg, 1 1 .8 mg, 12 mg, 12.2 mg, 12.4 mg, 12.6 mg,

12.8 mg, 13 mg, 13.2 mg, 13.4 mg, 13.6 mg, 13.8 mg, 14 mg, 14.2 mg, 14.4 mg, 14.6 mg, 14.8 mg,

15 mg, 15.2 mg, 15.4 mg, 15.6 mg, 15.8 mg, 16 mg, 16.2 mg, 16.4 mg, 16.6 mg, 16.8 mg, 17 mg,

18.2 mg, 18.4 mg, 18.6 mg, 18.8 mg, 19 mg, 19.2 mg, 19.4 mg, 19.6 mg, or 19.8 mg). In some aspects, the C1 D2 is between 3.2 mg to 10 mg. In some aspects, the C1 D2 is 3.6 mg. In some aspects, the C1 D3 is between about 20 mg to about 600 mg (e.g., between about 30 mg to about 500 mg, about 40 mg to about 400 mg, about 60 mg to about 350 mg, about 80 mg to about 300 mg, about 100 mg to about 200 mg, or about 140 mg to about 180 mg, e.g., about 20, 40, 60, 80, 100, 120, 140, 160, 180, 200, 220, 240, 260, 280, 300, 320, 340, 360, 380, 400, 420, 440, 460, 480, 500, 520, 540, 560, 580, or 600 mg). In some aspects, the C1 D3 is between about 80 mg to about 300 mg. In some aspects, the C1 D3 is about 160 mg.

In some aspects, the C1 D3 is between 20 mg to 600 mg (e.g., between 30 mg to 500 mg, 40 mg to 400 mg, 60 mg to 350 mg, 80 mg to 300 mg, 100 mg to 200 mg, or 140 mg to 180 mg, e.g., 20, 40, 60, 80, 100, 120, 140, 160, 180, 200, 220, 240, 260, 280, 300, 320, 340, 360, 380, 400, 420, 440, 460, 480, 500, 520, 540, 560, 580, or 600 mg). In some aspects, the C1 D3 is between 80 mg to 300 mg. In some aspects, the C1 D3 is 160 mg.

In some aspects, the method comprises only a single dosing cycle (e.g., a dosing cycle comprising a C1 D1 , a C1 D2, and a C1 D3). In other aspects, the dosing regimen further comprises a second dosing cycle comprising at least a single dose (C2D1 ) of the bispecific antibody. In some aspects, the C2D1 is equal to or greater than the C1 D3 and is between about 20 mg to about 600 mg (e.g., between about 30 mg to about 500 mg, about 40 mg to about 400 mg, about 60 mg to about 350 mg, about 80 mg to about 300 mg, about 100 mg to about 200 mg, or about 140 mg to about 180 mg, e.g., about 20, 40, 60, 80, 100, 120, 140, 160, 180, 200, 220, 240, 260, 280, 300, 320, 340, 360, 380, 400, 420, 440, 460, 480, 500, 520, 540, 560, 580, or 600 mg). In some aspects, the C2D1 is between about 80 mg to about 300 mg. In some aspects, the C2D1 is about 160 mg.

In some aspects, the C2D1 is between 20 mg to 600 mg (e.g., between 30 mg to 500 mg, 40 mg to 400 mg, 60 mg to 350 mg, 80 mg to 300 mg, 100 mg to 200 mg, or 140 mg to 180 mg, e.g., 20, 40, 60, 80, 100, 120, 140, 160, 180, 200, 220, 240, 260, 280, 300, 320, 340, 360, 380, 400, 420, 440, 460, 480, 500, 520, 540, 560, 580, or 600 mg). In some aspects, the C2D1 is between 80 mg to 300 mg. In some aspects, the C2D1 is 160 mg. In some aspects, the C2D1 is 159 mg.

Alternatively, in any of the above embodiments, the C1 D1 may be between about 0.01 mg to about 60 mg (e.g., between about 0.05 mg to about 50 mg, between about 0.01 mg to about 40 mg, between about 0.1 mg to about 20 mg, between about 0.1 mg to about 10 mg, between about 0.1 mg to about 5 mg, between about 0.1 mg to about 2 mg, between about 0.1 mg to about 1 .5 mg, between about 0.1 mg to about 1 .2 mg, between about 0.1 mg to about 0.5mg, or between about 0.2 mg to about 0.4 mg, e.g., about 0.3 mg, e.g., 0.3 mg), the C1 D2 may be between about 0.05 mg to about 180 mg (e.g., between about 0.1 mg to about 160 mg, between about 0.5 mg to about 140 mg, between about 1 mg to about 120 mg, between about 1 .5 mg to about 100 mg, between about 2.0 mg to about 80 mg, between about 2.5 mg to about 50 mg, between about 3.0 mg to about 25 mg, between about 3.0 mg to about 15 mg, between about 3.0 mg to about 10 mg, between about 3.0 mg to about 5 mg, or between about 3.0 mg to about 4.0 mg, e.g., about 3.6 mg, e.g., 3.6 mg), and the C1 D3 may be between about 0.15 mg to about 1000 mg (e.g., between about 0.5 mg to about 800 mg, between about 1 mg to about 700 mg, between about 5 mg to about 500 mg, between about 10 mg to about 400 mg, between about 25 mg to about 300 mg, between about 40 mg to about 200 mg, between about 50 mg to about 190 mg, between about 140 mg to about 180 mg, or between about 150 mg to about 170 mg, e.g., about 160 mg, e.g., 160 mg); and in aspects comprising a second dosing cycle, the C2D1 may be between about 0.15 mg to about 1000 mg (e.g., between about 0.5 mg to about 800 mg, between about 1 mg to about 700 mg, between about 5 mg to about 500 mg, between about 10 mg to about 400 mg, between about 25 mg to about 300 mg, between about 40 mg to about 200 mg, between about 50 mg to about 190 mg, between about 140 mg to about 180 mg, or between about 150 mg to about 170 mg, e.g., about 160 mg, e.g., 160 mg).

In some instances, the length of the first dosing cycle is three weeks or 21 days. In some instances, the methods may include administering to the subject the C1 D1 , the C1 D2, and the C1 D3 on or about Days 1 , 8, and 15, respectively, of the first dosing cycle.

Further dosing cycles

In some instances, the methods described above may include a second dosing cycle of three weeks or 21 days. In some instances, the methods may include administering to the subject the C2D1 on or about Day 1 of the second dosing cycle.

In some instances in which the methods include at least a second dosing cycle, the methods may include one or more additional dosing cycles. In some instances, the dosing regimen comprises 1 to 17 additional dosing cycles (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, or 17 additional dosing cycles, e.g., 1 -3 additional dosing cycles, 1 -5 additional dosing cycles, 3-8 additional dosing cycles, 5-10 additional dosing cycles, 8-12 additional dosing cycles, 10-15 additional dosing cycles, 12-17 additional dosing cycles, or 15-17 additional dosing cycles, i.e., the dosing regimen includes one or more of additional dosing cycle(s) C3, C4, C5, C6, C7, C8, C9, C10, C11 , C12, C13, C14, C15, C16, C17, C18, and C19. In some embodiments, the length of each of the one or more additional dosing cycles is 7 days, 14 days, 21 days, or 28 days. In some embodiments, the length of each of the one or more additional dosing cycles is between 5 days and 30 days, e.g., between 5 and 9 days, between 7 and 11 days, between 9 and 13 days, between 11 and 15 days, between 13 and 17 days, between 15 and 19 days, between 17 and 21 days, between 19 and 23 days, between 21 and 25 days, between 23 and 27 days, or between 25 and 30 days. In some instances, the length of each of the one or more additional dosing cycles is three weeks or 21 days. In some instances, each of the one or more additional dosing cycles comprises a single dose of the bispecific antibody. In some aspects, the dose of the bispecific antibody in the one or more additional dosing cycles is equal to the C2D1 , e.g., is between about 20 mg to about 600 mg (e.g., between about 30 mg to about 500 mg, about 40 mg to about 400 mg, about 60 mg to about 350 mg, about 80 mg to about 300 mg, about 100 mg to about 200 mg, or about 140 mg to about 180 mg, e.g., about 20, 40, 60, 80, 100, 120, 140, 160, 180, 200, 220, 240, 260, 280, 300, 320, 340, 360, 380, 400, 420, 440, 460, 480, 500, 520, 540, 560, 580, or 600 mg). In some aspects, the dose of the bispecific antibody in the one or more additional dosing cycles is about 160 mg. In some aspects, the dose of the bispecific antibody in the one or more additional dosing cycles is about 198 mg. In some aspects, the dose of the bispecific antibody in the one or more additional dosing cycles is equal to the C2D1 , e.g., is between 20 mg to 600 mg (e.g., between 30 mg to 500 mg, 40 mg to 400 mg, 60 mg to 350 mg, 80 mg to 300 mg, 100 mg to 200 mg, or 140 mg to 180 mg, e.g., 20, 40, 60, 80, 100, 120, 140, 160, 180, 200, 220, 240, 260, 280, 300, 320, 340, 360, 380, 400, 420, 440, 460, 480, 500, 520, 540, 560, 580, or 600 mg). In some aspects, the dose of the bispecific antibody in the one or more additional dosing cycles is 160 mg. In some aspects, the dose of the bispecific antibody in the one or more additional dosing cycles is 198 mg. In some instances, the method comprises administering to the subject the single dose of the bispecific antibody on or about Day 1 of the one or more additional dosing cycles.

In some aspects, the bispecific antibody is administered to the subject every 21 days (Q3W) until progressive disease is observed, for up to 18 cycles, or until minimal residual disease (MRD) is observed.

In some instances, the bispecific anti-FcRH5/anti-CD3 antibody is administered to the subject as a monotherapy.

V. COMBINATION THERAPIES

In some instances, the bispecific anti-FcRH5/anti-CD3 antibody is administered to the subject in a combination therapy. For example, the bispecific anti-FcRH5/anti-CD3 antibody may be coadministered with one or more additional therapeutic agents.

/. Tocilizumab and treatment of CRS

In one instance, the additional therapeutic agent is an effective amount of tocilizumab (ACTEMRA®). In some instances, the subject has a cytokine release syndrome (CRS) event (e.g., has a CRS event following treatment with the bispecific antibody, e.g., has a CRS event following a C1 D1 , a C1 D2, a C1 D3, a C2D1 , or an additional dose of the bispecific antibody), and the method further comprises treating the symptoms of the CRS event (e.g., treating the CRS event by administering to the subject an effective amount of tocilizumab) while suspending treatment with the bispecific antibody. In some aspects, tocilizumab is administered intravenously to the subject as a single dose of about 8 mg/kg. In some aspects, the CRS event does not resolve or worsens within 24 hours of treating the symptoms of the CRS event, and the method further comprising administering to the subject one or more additional doses of tocilizumab to manage the CRS event, e.g., administering one or more additional doses of tocilizumab intravenously to the subject at a dose of about 8 mg/kg.

In some aspects, treating the symptoms of the CRS event further comprises treatment with a high-dose vasopressor (e.g., norepinephrine, dopamine, phenylephrine, epinephrine, or vasopressin and norepinephrine).

In other instances, tocilizumab is administered as a premedication, e.g., is administered to the subject prior to the administration of the bispecific anti-FcRH5/anti-CD3 antibody. In some instances, tocilizumab is administered as a premedication in Cycle 1 , e.g., is administered prior to a first dose (C1 D1 ), a second dose (C1 D2), and/or a third dose (C1 D3) of the bispecific anti-FcRH5/anti-CD3 antibody. In some aspects, the tocilizumab is administered intravenously to the subject as a single dose of about 8 mg/kg. CRS symptoms and grading

CRS may be graded according to the Modified Cytokine Release Syndrome Grading System established by Lee et al., Blood, 124: 188-195, 2014 or Lee et al., Biol Blood Marrow Transplant, 25(4): 625-638, 2019, as described in Table 12A. In addition to diagnostic criteria, recommendations on management of CRS based on its severity, including early intervention with corticosteroids and/or anti-cytokine therapy, are provided and referenced in Table 12A and Table 12B.

Mild to moderate presentations of CRS and/or infusion-related reaction (IRR) may include symptoms such as fever, headache, and myalgia, and may be treated symptomatically with analgesics, anti-pyretics, and antihistamines as indicated. Severe or life-threatening presentations of CRS and/or IRR, such as hypotension, tachycardia, dyspnea, or chest discomfort should be treated aggressively with supportive and resuscitative measures as indicated, including the use of high-dose corticosteroids, IV fluids, admission to intensive care unit, and other supportive measures. Severe CRS may be associated with other clinical sequelae such as disseminated intravascular coagulation, capillary leak syndrome, or macrophage activation syndrome (MAS). Standard of care for severe or life threatening CRS resulting from immune-based therapy has not been established; case reports and recommendations using anti-cytokine therapy such as tocilizumab have been published (Teachey et al., Blood, 121 : 5154-5157, 2013; Lee et al., Blood, 124: 188-195, 2014; Maude et al., New Engl J Med, 371 : 1507-1517, 2014).

As noted in Table 12A, even moderate presentations of CRS in subjects with extensive comorbidities should be monitored closely, with consideration given to intensive care unit admission and tocilizumab administration.

Administration of tocilizumab as a premedication

In some aspects, an effective amount of tocilizumab is administered as a premedication (prophylaxis), e.g., is administered to the subject prior to the administration of the bispecific antibody (e.g., administered about 2 hours prior to the administration of the bispecific antibody). Administration of tocilizumab as a premedication may reduce the frequency or severity of CRS. In some aspects, tocilizumab is administered as a premedication in Cycle 1 , e.g., is administered prior to a first dose (C1 D1 ; cycle 1 , dose 1 ), a second dose (C1 D2; cycle 1 , dose, 2), and/or a third dose (C1 D3; cycle 1 , dose 3) of the bispecific antibody. In some aspects, the tocilizumab is administered intravenously to the subject as a single dose of about 1 mg/kg to about 15 mg/kg, e.g., about 4 mg/kg to about 10 mg/kg, e.g., about 6 mg/kg to about 10 mg/kg, e.g., about 8 mg/kg. In some aspects, the tocilizumab is administered intravenously to the subject as a single dose of about 8 mg/kg. In some aspects, the tocilizumab is administered intravenously to the subject as a single dose of about 8 mg/kg for patients weighing 30 kg or more (maximum 800 mg) and at a dose of about 12 mg/kg for patients weighing less than 30 kg. Other anti-IL-6R antibodies that could be used in combination with tocilizumab include sarilumab, vobarilizumab (ALX-0061 ), SA-237, and variants thereof. For example, in one aspect, the bispecific antibody is co-administered with tocilizumab (ACTEMRA® / ROACTEMRA®), wherein the subject is first administered with tocilizumab (ACTEMRA® / ROACTEMRA®) and then separately administered with the bispecific antibody (e.g., the subject is pre-treated with tocilizumab (ACTEMRA® / ROACTEMRA®)).

In some aspects, the incidence of CRS (e.g., Grade 1 CRS, Grade 2 CRS, and/or Grade 3+ CRS) is reduced in patients who are treated with tocilizumab as a premedication relative to patients who are not treated with tocilizumab as a premedication. In some aspects, less intervention to treat CRS (e.g., less need for additional tocilizumab, IV fluids, steroids, or O2) is required in patients who are treated with tocilizumab as a premedication relative to patients who are not treated with tocilizumab as a premedication. In some aspects, CRS symptoms have decreased severity (e.g., are limited to fevers and rigors) in patients who are treated with tocilizumab as a premedication relative to patients who are not treated with tocilizumab as a premedication.

Tocilizumab administered to treat CRS

In some aspects, the subject experiences a CRS event during treatment with the therapeutic bispecific antibody and an effective amount of tocilizumab is administered to manage the CRS event.

In some aspects, the subject has a CRS event (e.g., has a CRS event following treatment with the bispecific antibody, e.g., has a CRS event following a first dose or a subsequent dose of the bispecific antibody), and the method further includes treating the symptoms of the CRS event while suspending treatment with the bispecific antibody.

In some aspects, the subject experiences a CRS event, and the method further includes administering to the subject an effective amount of an interleukin-6 receptor (IL-6R) antagonist (e.g., an anti-IL-6R antibody, e.g., tocilizumab (ACTEMRA® / ROACTEMRA®)) to manage the CRS event while suspending treatment with the bispecific antibody. In some aspects, the IL-6R antagonist (e.g., tocilizumab) is administered intravenously to the subject as a single dose of about 1 mg/kg to about 15 mg/kg, e.g., about 4 mg/kg to about 10 mg/kg, e.g., about 6 mg/kg to about 10 mg/kg, e.g., about 8 mg/kg. In some aspects, the tocilizumab is administered intravenously to the subject as a single dose of about 8 mg/kg. Other anti-IL-6R antibodies that could be used in combination with tocilizumab include sarilumab, vobarilizumab (ALX-0061 ), SA-237, and variants thereof.

In some aspects, the CRS event does not resolve or worsens within 24 hours of treating the symptoms of the CRS event, and the method further includes administering to the subject one or more additional doses of the IL-6R antagonist (e.g., an anti-IL-6R antibody, e.g., tocilizumab) to manage the CRS event, e.g., administering one or more additional doses of tocilizumab intravenously to the subject at a dose of about 1 mg/kg to about 15 mg/kg, e.g., about 4 mg/kg to about 10 mg/kg, e.g., about 6 mg/kg to about 10 mg/kg, e.g., about 8 mg/kg. In some aspects, the one or more additional doses of tocilizumab are administered intravenously to the subject as a single dose of about 8 mg/kg.

In some aspects, the method further includes administering to the subject an effective amount of a corticosteroid. The corticosteroid may be administered intravenously to the subject. In some aspects, the corticosteroid is methylprednisone (methylprednisolone). In some instances, the methylprednisone is administered at a dose of about 1 mg/kg per day to about 5 mg/kg per day, e.g., about 2 mg/kg per day. In some instances, the corticosteroid is dexamethasone. In some instances, the dexamethasone is administered at a dose of about 10 mg (e.g., a single dose of about 10 mg intravenously) or at a dose of about 0.5 mg/kg/day.

The subject may be administered a corticosteroid, such as methylprednisolone or dexamethasone, if the CRS event is not managed with administration of the IL-6R antagonist (e.g., tocilizumab) alone. In some aspects, treating the symptoms of the CRS event further includes treatment with a high-dose vasopressor (e.g., norepinephrine, dopamine, phenylephrine, epinephrine, or vasopressin and norepinephrine), e.g., as described in Table 12A and Table 12B. Table 1 1 provides details about tocilizumab treatment of severe or life-threatening CRS.

Management of CRS events by grade

Management of the CRS events may be tailored based on the grade of the CRS (Table 1 1 and Table 12A) and the presence of comorbidities. Table 1 1 provides recommendations for the management of CRS syndromes by grade.

Table 11. Recommendations for management of cytokine release syndrome

CRS = cytokine release syndrome; HLH = hemophagocytic lymphohistiocytosis; ICU = intensive care unit; IV = intravenous; MAS = macrophage activation syndrome.

Note: CRS is a disorder characterized by nausea, headache, tachycardia, hypotension, rash, shortness of breath, and renal, coagulation, hepatic and neurologic disorders; it is caused by the release of cytokines from cells (Lee et al., Blood, 124: 188-195, 2014). a Refer to Table 12A for description of grading of symptoms. b Guidance for CRS management based on Lee et al., Blood, 124: 188-195, 2014. c Refer to Table 12B for a description and calculation of high-dose vasopressors. d If the patient does not experience CRS during the next infusion at the 50% reduced rate, the infusion rate can be increased to the initial rate in subsequent cycles. However, if this patient experiences another CRS event, the infusion rate should be reduced by 25%-50% depending on the severity of the event.

Table 12A. Cytokine release syndrome grading systems

Lee 2014 criteria: Lee et al., Blood, 124: 188-195, 2014.

ASTCT consensus grading: Lee et al., Biol Blood Marrow Transplant, 25(4): 625-638, 2019. a Low-dose vasopressor: single vasopressor at doses below that shown in Table 12B. b High-dose vasopressor: as defined in Table 12B.

*Fever is defined as temperature >38°C not attributable to any other cause. In patients who have CRS then receive antipyretic or anticytokine therapy such as tocilizumab or steroids, fever is no longer required to grade subsequent CRS severity. In this case, CRS grading is driven by hypotension and/or hypoxia. tCRS grade is determined by the more severe event: hypotension or hypoxia not attributable to any other cause. For example, a patient with temperature of 39.5°C, hypotension requiring 1 vasopressor, and hypoxia requiring low-flow nasal cannula is classified as grade 3 CRS. :Low-flow nasal cannula is defined as oxygen delivered at <6L/minute. Low flow also includes blowby oxygen delivery, sometimes used in pediatrics. High-flow nasal cannula is defined as oxygen delivered at >6L/minute.

Table 12B. High-dose vasopressors

min = minute; VASST = Vasopressin and Septic Shock Trial. a VASST vasopressor equivalent equation: norepinephrine equivalent dose = [norepinephrine (pg /min)] + [dopamine (pg /kg/min) - 2] + [epinephrine (pg /min)] + [phenylephrine (pg /min) - 10].

Management of Grade 2 CRS events

If the subject has a grade 2 CRS event (e.g., a grade 2 CRS event in the absence of comorbidities or in the presence of minimal comorbidities) following administration of the therapeutic bispecific antibody, the method may further include treating the symptoms of the grade 2 CRS event while suspending treatment with the bispecific antibody. If the grade 2 CRS event then resolves to a grade < 1 CRS event for at least three consecutive days, the method may further include resuming treatment with the bispecific antibody without altering the dose. On the other hand, if the grade 2 CRS event does not resolve or worsens to a grade > 3 CRS event within 24 hours of treating the symptoms of the grade 2 CRS event, the method may further involve administering to the subject an effective amount of an interleukin-6 receptor (IL-6R) antagonist (e.g., an anti-IL-6R antibody, e.g., tocilizumab (ACTEMRA® I ROACTEMRA®)) to manage the grade 2 or grade > 3 CRS event. In some instances, tocilizumab is administered intravenously to the subject as a single dose of about 8 mg/kg. Other anti-IL-6R antibodies that could be used in combination with tocilizumab include sarilumab, vobarilizumab (ALX-0061 ), SA-237, and variants thereof.

If the subject has a grade 2 CRS event in the presence of extensive comorbidities following administration of the therapeutic bispecific antibody, the method may further include administering to the subject a first dose of an IL-6R antagonist (e.g., an anti-IL-6R antibody, e.g., tocilizumab (ACTEMRA® I ROACTEMRA®)) to manage the grade 2 CRS event while suspending treatment with the bispecific antibody. In some instances, the first dose of tocilizumab is administered intravenously to the subject at a dose of about 8 mg/kg. Other anti-IL-6R antibodies that could be used in combination with tocilizumab include sarilumab, vobarilizumab (ALX-0061 ), SA-237, and variants thereof. In some instances, if the grade 2 CRS event resolves to a grade < 1 CRS event within two weeks, the method further includes resuming treatment with the bispecific antibody at a reduced dose. In some instances, the reduced dose is 50% of the initial infusion rate of the previous cycle if the event occurred during or within 24 hours of the infusion. If, on the other hand, the grade 2 CRS event does not resolve or worsens to a grade > 3 CRS event within 24 hours of treating the symptoms of the grade 2 CRS event, the method may further include administering to the subject one or more (e.g., one, two, three, four, or five or more) additional doses of an IL-6R antagonist (e.g., an anti-IL-6R antibody, e.g., tocilizumab) to manage the grade 2 or grade > 3 CRS event. In some particular instances, the grade 2 CRS event does not resolve or worsens to a grade > 3 CRS event within 24 hours of treating the symptoms of the grade 2 CRS event, and the method may further include administering to the subject one or more additional doses of tocilizumab to manage the grade 2 or grade > 3 CRS event. In some instances, the one or more additional doses of tocilizumab is administered intravenously to the subject at a dose of about 1 mg/kg to about 15 mg/kg, e.g., about 4 mg/kg to about 10 mg/kg, e.g., about 6 mg/kg to about 10 mg/kg, e.g., about 8 mg/kg. In some instances, the method further includes administering to the subject an effective amount of a corticosteroid. The corticosteroid may be administered before, after, or concurrently with the one or more additional doses of tocilizumab or other anti-IL-6R antibody. In some instances, the corticosteroid is administered intravenously to the subject. In some instances, the corticosteroid is methylprednisolone. In some instances, the methylprednisolone is administered at a dose of about 1 mg/kg per day to about 5 mg/kg per day, e.g., about 2 mg/kg per day. In some instances, the corticosteroid is dexamethasone. In some instances, the dexamethasone is administered at a dose of about 10 mg (e.g., a single dose of about 10 mg intravenously) or at a dose of about 0.5 mg/kg/day.

Management of Grade 3 CRS events

If the subject has a grade 3 CRS event following administration of the therapeutic bispecific antibody, the method may further include administering to the subject a first dose of an IL-6R antagonist (e.g., an anti-IL-6R antibody, e.g., tocilizumab (ACTEMRA® / ROACTEMRA®)) to manage the grade 3 CRS event while suspending treatment with the bispecific antibody. In some instances, the first dose of tocilizumab is administered intravenously to the subject at a dose of about 8 mg/kg. Other anti-IL-6R antibodies that could be used in combination with tocilizumab include sarilumab, vobarilizumab (ALX-0061 ), SA-237, and variants thereof. In some instances, the subject recovers (e.g., is afebrile and off vasopressors) within 8 hours following treatment with the bispecific antibody, and the method further includes resuming treatment with the bispecific antibody at a reduced dose. In some instances, the reduced dose is 50% of the initial infusion rate of the previous cycle if the event occurred during or within 24 hours of the infusion. In other instances, if the grade 3 CRS event does not resolve or worsens to a grade 4 CRS event within 24 hours of treating the symptoms of the grade 3 CRS event, the method may further include administering to the subject one or more (e.g., one, two, three, four, or five or more) additional doses of an IL-6R antagonist (e.g., an anti-IL-6R antibody, e.g., tocilizumab) to manage the grade 3 or grade 4 CRS event. In some particular instances, the grade 3 CRS event does not resolve or worsens to a grade 4 CRS event within 24 hours of treating the symptoms of the grade 3 CRS event, and the method further includes administering to the subject one or more additional doses of tocilizumab to manage the grade 3 or grade 4 CRS event. In some instances, the one or more additional doses of tocilizumab is administered intravenously to the subject at a dose of about 1 mg/kg to about 15 mg/kg, e.g., about 4 mg/kg to about 10 mg/kg, e.g., about 6 mg/kg to about 10 mg/kg, e.g., about 8 mg/kg. In some instances, the method further includes administering to the subject an effective amount of a corticosteroid. The corticosteroid may be administered before, after, or concurrently with the one or more additional doses of tocilizumab or other anti-IL-6R antibody. In some instances, the corticosteroid is administered intravenously to the subject. In some instances, the corticosteroid is methylprednisolone. In some instances, the methylprednisolone is administered at a dose of about 1 mg/kg per day to about 5 mg/kg per day, e.g., about 2 mg/kg per day. In some instances, the corticosteroid is dexamethasone. In some instances, the dexamethasone is administered at a dose of about 10 mg (e.g., a single dose of about 10 mg intravenously) or at a dose of about 0.5 mg/kg/day.

Management of Grade 4 CRS events

If the subject has a grade 4 CRS event following administration of the therapeutic bispecific antibody, the method may further include administering to the subject a first dose of an IL-6R antagonist (e.g., an anti-IL-6R antibody, e.g., tocilizumab (ACTEMRA® / ROACTEMRA®)) to manage the grade 4 CRS event and permanently discontinuing treatment with the bispecific antibody. In some instances, the first dose of tocilizumab is administered intravenously to the subject at a dose of about 8 mg/kg. Other anti-IL-6R antibodies that could be used in combination with tocilizumab include sarilumab, vobarilizumab (ALX-0061 ), SA-237, and variants thereof. The grade 4 CRS event may, in some instances, resolve within 24 of treating the symptoms of the grade 4 CRS event. If the grade 4 CRS event does not resolve within 24 hours of treating the symptoms of the grade 4 CRS event, the method may further include administering to the subject one or more additional doses of an IL-6R antagonist (e.g., an anti-IL-6R antibody, e.g., tocilizumab (ACTEMRA® / ROACTEMRA®)) to manage the grade 4 CRS event. In some particular instances, the grade 4 CRS event does not resolve within 24 hours of treating the symptoms of the grade 4 CRS event, and the method further includes administering to the subject one or more (e.g., one, two, three, four, or five or more) additional doses of tocilizumab to manage the grade 4 CRS event. In some instances, the one or more additional doses of tocilizumab is administered intravenously to the subject at a dose of about 1 mg/kg to about 15 mg/kg, e.g., about 4 mg/kg to about 10 mg/kg, e.g., about 6 mg/kg to about 10 mg/kg, e.g., about 8 mg/kg. In some instances, the method further includes administering to the subject an effective amount of a corticosteroid. The corticosteroid may be administered before, after, or concurrently with the one or more additional doses of tocilizumab or other anti-IL-6R antibody. In some instances, the corticosteroid is administered intravenously to the subject. In some instances, the corticosteroid is methylprednisolone. In some instances, the methylprednisolone is administered at a dose of about 1 mg/kg per day to about 5 mg/kg per day, e.g., about 2 mg/kg per day. In some instances, the corticosteroid is dexamethasone. In some instances, the dexamethasone is administered at a dose of about 10 mg (e.g., a single dose of about 10 mg intravenously) or at a dose of about 0.5 mg/kg/day.

/. Corticosteroids

In another instance, the additional therapeutic agent is an effective amount of a corticosteroid. The corticosteroid may be administered intravenously to the subject. In some aspects, the corticosteroid is methylprednisone. The methylprednisone may be administered to the subject at a dose of about 80 mg. In other aspects, the corticosteroid is dexamethasone. The dexamethasone may be administered to the subject at a dose of about 80 mg. In some aspects, the corticosteroid (e.g., methylprednisone or dexamethasone) is administered to the subject prior to the administration of the bispecific anti-FcRH5/anti-CD3 antibody, e.g., administered one hour prior to the administration of the bispecific anti-FcRH5/anti-CD3 antibody.

/'/. Acetaminophen or paracetamol

In another instance, the additional therapeutic agent is an effective amount of acetaminophen or paracetamol. The acetaminophen or paracetamol may be administered orally to the subject, e.g., administered orally at a dose of between about 500 mg to about 1000 mg. In some aspects, the acetaminophen or paracetamol is administered to the subject as a premedication, e.g., is administered prior to the administration of the bispecific anti-FcRH5/anti-CD3 antibody.

Hi. Diphenhydramine

In another instance, the additional therapeutic agent is an effective amount of diphenhydramine. The diphenhydramine may be administered orally to the subject, e.g., administered orally at a dose of between about 25 mg to about 50 mg. In some aspects, the diphenhydramine is administered to the subject as a premedication, e.g., is administered prior to the administration of the bispecific anti-FcRH5/anti-CD3 antibody. iv. Anti-myeloma agents

In another instance, the additional therapeutic agent is an effective amount of an antimyeloma agent, e.g., an anti-myeloma agent that augments and/or complements T-cell-mediated killing of myeloma cells. The anti-myeloma agent may be, e.g., pomalidomide, daratumumab, and/or a B-cell maturation antigen (BCMA)-directed therapy (e.g., an antibody-drug conjugate targeting BCMA (BCMA-ADC)). In some aspects, the anti-myeloma agent is administered in four-week cycles. In some aspects, the anti-myeloma agent is pomalidomide. In some aspects, the pomalidomide is administered orally at a dose of 4 mg on days 1 -28 of a 28-day cycle. In some aspects, the pomalidomide is administered in combination with dexamethasone, e.g., administered in combination with dexamethasone administered on days 1 , 8, 15, and 22 of a 28-day cycle.

In some aspects, the anti-myeloma agent is daratumumab. In some aspects, the daratumumab is administered by intravenous infusion (e.g., infusion over 3-5 hours) at a dose of 16 mg/kg once every week, once every two weeks, or once every four weeks. In some aspects, the daratumumab is administered by intravenous infusion (e.g., infusion over 3-5 hours) at a dose of 16 mg/kg once every week for two 28-day cycles, once every two weeks for three 28-day cycles, and once every four weeks for one or more additional cycles. v. Other combination therapies

In some aspects, the one or more additional therapeutic agents comprise a PD-1 axis binding antagonist, an immunomodulatory agent, an anti-neoplastic agent, a chemotherapeutic agent, a growth inhibitory agent, an anti-angiogenic agent, a radiation therapy, a cytotoxic agent, a cell-based therapy, or a combination thereof.

PD- 1 axis binding antagonists

In some aspects, the additional therapeutic agent is a PD-1 axis binding antagonist. Exemplary PD-1 axis binding antagonists include agents that inhibit the interaction of a PD-L1 axis binding partner with one or more of its binding partners, so as to remove T cell dysfunction resulting from signaling on the PD-1 signaling axis, with a result being to restore or enhance T cell function (e.g., proliferation, cytokine production, target cell killing). As used herein, a PD-1 axis binding antagonist includes a PD-1 binding antagonist, a PD-L1 binding antagonist, and a PD-L2 binding antagonist.

Growth inhibitory agents

In some aspects, the additional therapeutic agent is a growth inhibitory agent. Exemplary growth inhibitory agents include agents that block cell cycle progression at a place other than S phase, e.g., agents that induce G1 arrest (e.g., DNA alkylating agents such as tamoxifen, prednisone, dacarbazine, mechlorethamine, cisplatin, methotrexate, 5-fluorouracil, or ara-C) or M-phase arrest (e.g., vincristine, vinblastine, taxanes (e.g., paclitaxel and docetaxel), doxorubicin, epirubicin, daunorubicin, etoposide, or bleomycin).

Radiation therapies

In some aspects, the additional therapeutic agent is a radiation therapy. Radiation therapies include the use of directed gamma rays or beta rays to induce sufficient damage to a cell so as to limit its ability to function normally or to destroy the cell altogether. Typical treatments are given as a onetime administration and typical dosages range from 10 to 200 units (Grays) per day. Cytotoxic agents

In some aspects, the additional therapeutic agent is a cytotoxic agent, e.g., a substance that inhibits or prevents a cellular function and/or causes cell death or destruction. Cytotoxic agents include, but are not limited to, radioactive isotopes (e.g., At²¹¹ , 1¹³¹ , I¹²⁵, Y⁹⁰, Re¹⁸⁶, Re¹⁸⁸, Sm¹⁵³, Bi²¹², P³², Pb²¹², and radioactive isotopes of Lu); chemotherapeutic agents or drugs (e.g., methotrexate, adriamicin, vinca alkaloids (vincristine, vinblastine, etoposide), doxorubicin, melphalan, mitomycin C, chlorambucil, daunorubicin or other intercalating agents); growth inhibitory agents; enzymes and fragments thereof such as nucleolytic enzymes; antibiotics; toxins such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including fragments and/or variants thereof; and antitumor or anticancer agents.

Anti-cancer therapies

In some instances, the methods include administering to the individual an anti-cancer therapy other than, or in addition to, a bispecific anti-FcRH5/anti-CD3 antibody (e.g., an anti-neoplastic agent, a chemotherapeutic agent, a growth inhibitory agent, an anti-angiogenic agent, a radiation therapy, or a cytotoxic agent).

In some instances, the methods further involve administering to the patient an effective amount of an additional therapeutic agent. In some instances, the additional therapeutic agent is selected from the group consisting of an anti-neoplastic agent, a chemotherapeutic agent, a growth inhibitory agent, an anti-angiogenic agent, a radiation therapy, a cytotoxic agent, and combinations thereof. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with a chemotherapy or chemotherapeutic agent. In some instances, a bispecific anti- FcRH5/anti-CD3 antibody may be administered in conjunction with a radiation therapy agent. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with a targeted therapy or targeted therapeutic agent. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with an immunotherapy or immunotherapeutic agent, for example a monoclonal antibody. In some instances, the additional therapeutic agent is an agonist directed against a co-stimulatory molecule. In some instances, the additional therapeutic agent is an antagonist directed against a co-inhibitory molecule.

Without wishing to be bound to theory, it is thought that enhancing T-cell stimulation, by promoting a co-stimulatory molecule or by inhibiting a co-inhibitory molecule, may promote tumor cell death thereby treating or delaying progression of cancer. In some instances, a bispecific anti- FcRH5/anti-CD3 antibody may be administered in conjunction with an agonist directed against a co- stimulatory molecule. In some instances, a co-stimulatory molecule may include CD40, CD226, CD28, 0X40, GITR, CD137, CD27, HVEM, or CD127. In some instances, the agonist directed against a co-stimulatory molecule is an agonist antibody that binds to CD40, CD226, CD28, 0X40, GITR, CD137, CD27, HVEM, or CD127. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with an antagonist directed against a co-inhibitory molecule. In some instances, a co-inhibitory molecule may include CTLA-4 (also known as CD152), TIM-3, BTLA, VISTA, LAG-3, B7-H3, B7-H4, IDO, TIG IT, MICA/B, or arginase. In some instances, the antagonist directed against a co-inhibitory molecule is an antagonist antibody that binds to CTLA- 4, TIM-3, BTLA, VISTA, LAG-3, B7-H3, B7-H4, IDO, TIGIT, MICA/B, or arginase.

In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with an antagonist directed against CTLA-4 (also known as CD152), e.g., a blocking antibody. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with ipilimumab (also known as MDX-010, MDX-101 , or YERVOY®). In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with tremelimumab (also known as ticilimumab or CP-675,206). In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with an antagonist directed against B7-H3 (also known as CD276), e.g., a blocking antibody. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with MGA271 . In some instances, a bispecific anti-FcRH5/anti- CD3 antibody may be administered in conjunction with an antagonist directed against a TGF-beta, e.g., metelimumab (also known as CAT-192), fresolimumab (also known as GC1008), or LY2157299.

In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with a treatment comprising adoptive transfer of a T-cell (e.g., a cytotoxic T-cell or CTL) expressing a chimeric antigen receptor (CAR). In some instances, bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with a treatment comprising adoptive transfer of a T-cell comprising a dominant-negative TGF beta receptor, e.g., a dominant-negative TGF beta type II receptor. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with a treatment comprising a HERCREEM protocol (see, e.g., ClinicalTrials.gov Identifier NCT00889954).

In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with an agonist directed against CD137 (also known as TNFRSF9, 4-1 BB, or ILA), e.g., an activating antibody. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with urelumab (also known as BMS-663513). In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with an agonist directed against CD40, e.g., an activating antibody. In some instances, bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with CP-870893. In some instances, bispecific anti- FcRH5/anti-CD3 antibody may be administered in conjunction with an agonist directed against 0X40 (also known as CD134), e.g., an activating antibody. In some instances, a bispecific anti-FcRH5/anti- CD3 antibody may be administered in conjunction with an anti-OX40 antibody (e.g., AgonOX). In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with an agonist directed against CD27, e.g., an activating antibody. In some instances, a bispecific anti- FcRH5/anti-CD3 antibody may be administered in conjunction with CDX-1127. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with an antagonist directed against indoleamine-2,3-dioxygenase (IDO). In some instances, with the IDO antagonist is 1 -methyl-D-tryptophan (also known as 1 -D-MT). In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with an antibody-drug conjugate. In some instances, the antibody-drug conjugate comprises mertansine or monomethyl auristatin E (MMAE). In some instances, a bispecific anti- FcRH5/anti-CD3 antibody may be administered in conjunction with an anti-NaPi2b antibody-MMAE conjugate (also known as DNIB0600A or RG7599). In some instances, a bispecific anti-FcRH5/anti- CD3 antibody may be administered in conjunction with trastuzumab emtansine (also known as T- DM1 , ado-trastuzumab emtansine, or KADCYLA®, Genentech). In some instances, a bispecific anti- FcRH5/anti-CD3 antibody may be administered in conjunction with DMUC5754A. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with an antibody-drug conjugate targeting the endothelin B receptor (EDNBR), e.g., an antibody directed against EDNBR conjugated with MMAE.

In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with an anti-angiogenesis agent. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with an antibody directed against a VEGF, e.g., VEGF- A. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with bevacizumab (also known as AVASTIN®, Genentech). In some instances, a bispecific anti- FcRH5/anti-CD3 antibody may be administered in conjunction with an antibody directed against angiopoietin 2 (also known as Ang2). In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with MEDI3617.

In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with an antineoplastic agent. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with an agent targeting CSF-1 R (also known as M- CSFR or CD115). In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with anti-CSF-1 R (also known as IMC-CS4). In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with an interferon, for example interferon alpha or interferon gamma. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with Roferon-A (also known as recombinant Interferon alpha-2a). In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with GM-CSF (also known as recombinant human granulocyte macrophage colony stimulating factor, rhu GM-CSF, sargramostim, or LEUKINE®). In some instances, a bispecific anti- FcRH5/anti-CD3 antibody may be administered in conjunction with IL-2 (also known as aldesleukin or PROLEUKIN®). In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with IL-12. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with an antibody targeting CD20. In some instances, the antibody targeting CD20 is obinutuzumab (also known as GA101 or GAZYVA®) or rituximab. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with an antibody targeting GITR. In some instances, the antibody targeting GITR is TRX518.

In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with a cancer vaccine. In some instances, the cancer vaccine is a peptide cancer vaccine, which in some instances is a personalized peptide vaccine. In some instances the peptide cancer vaccine is a multivalent long peptide, a multi-peptide, a peptide cocktail, a hybrid peptide, or a peptide-pulsed dendritic cell vaccine (see, e.g., Yamada et al., Cancer Sci. 104:14-21 , 2013). In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with an adjuvant. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with a treatment comprising a TLR agonist, e.g., Poly-ICLC (also known as HILTONOL®), LPS, MPL, or CpG ODN. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with tumor necrosis factor (TNF) alpha. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with IL-1 . In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with HMGB1 . In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with an IL- 10 antagonist. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with an IL-4 antagonist. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with an IL-13 antagonist. In some instances, a bispecific anti- FcRH5/anti-CD3 antibody may be administered in conjunction with an HVEM antagonist. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with an ICOS agonist, e.g., by administration of ICOS-L, or an agonistic antibody directed against ICOS. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with a treatment targeting CX3CL1 . In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with a treatment targeting CXCL9. In some instances, a bispecific anti- FcRH5/anti-CD3 antibody may be administered in conjunction with a treatment targeting CXCL10. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with a treatment targeting CCL5. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with an LFA-1 or ICAM1 agonist. In some instances, a bispecific anti- FcRH5/anti-CD3 antibody may be administered in conjunction with a Selectin agonist.

In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with a targeted therapy. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with an inhibitor of B-Raf. In some instances, a bispecific anti- FcRH5/anti-CD3 antibody may be administered in conjunction with vemurafenib (also known as ZELBORAF®). In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with dabrafenib (also known as TAFINLAR®). In some instances, a bispecific anti- FcRH5/anti-CD3 antibody may be administered in conjunction with erlotinib (also known as TARCEVA®). In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with an inhibitor of a MEK, such as MEK1 (also known as MAP2K1 ) or MEK2 (also known as MAP2K2). In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with cobimetinib (also known as GDC-0973 or XL-518). In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with trametinib (also known as MEKINIST®). In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with an inhibitor of K-Ras. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with an inhibitor of c-Met. In some instances, a bispecific anti- FcRH5/anti-CD3 antibody may be administered in conjunction with onartuzumab (also known as MetMAb). In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with an inhibitor of Aik. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with AF802 (also known as CH5424802 or alectinib). In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with an inhibitor of a phosphatidylinositol 3-kinase (PI3K). In some instances, a bispecific anti-FcRH5/anti- CD3 antibody may be administered in conjunction with BKM120. In some instances, a bispecific anti- FcRH5/anti-CD3 antibody may be administered in conjunction with idelalisib (also known as GS-1101 or CAL-101 ). In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with perifosine (also known as KRX-0401 ). In some instances, a bispecific anti- FcRH5/anti-CD3 antibody may be administered in conjunction with an inhibitor of an Akt. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with MK2206. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with GSK690693. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with GDC-0941 . In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with an inhibitor of mTOR. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with sirolimus (also known as rapamycin). In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with temsirolimus (also known as CCI-779 or TORISEL®). In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with everolimus (also known as RAD001 ). In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with ridaforolimus (also known as AP-23573, MK-8669, or deforolimus). In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with OSI-027. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with AZD8055. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with INK128. In some instances, a bispecific anti- FcRH5/anti-CD3 antibody may be administered in conjunction with a dual PI3K/mTOR inhibitor. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with XL765. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with GDC-0980. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with BEZ235 (also known as NVP-BEZ235). In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with BGT226. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with GSK2126458. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with PF-04691502. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with PF-05212384 (also known as PKI-587).

In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with a chemotherapeutic agent. A chemotherapeutic agent is a chemical compound useful in the treatment of cancer. Exemplary chemotherapeutic agents include, but are not limited to erlotinib (TARCEVA®, Genentech/OSI Pharm.), anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens and selective estrogen receptor modulators (SERMs), antibodies such as alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech); cetuximab (ERBITUX®, Imclone); panitumumab (VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech/Biogen Idee), pertuzumab (OMNITARG®, 2C4, Genentech), or trastuzumab (HERCEPTIN®, Genentech), EGFR inhibitors (EGFR antagonists), tyrosine kinase inhibitors, and chemotherapeutic agents also include non-steroidal anti-inflammatory drugs (NSAIDs) with analgesic, antipyretic and anti-inflammatory effects.

In instances for which the methods described herein involve a combination therapy, such as a particular combination therapy noted above, the combination therapy encompasses the coadministration of the bispecific anti-FcRH5/anti-CD3 antibody with one or more additional therapeutic agents, and such co-administration may be combined administration (where two or more therapeutic agents are included in the same or separate formulations) or separate administration, in which case, administration of the bispecific anti-FcRH5/anti-CD3 antibody can occur prior to, simultaneously, and/or following, administration of the additional therapeutic agent or agents. In one embodiment, administration of the bispecific anti-FcRH5/anti-CD3 antibody and administration of an additional therapeutic agent or exposure to radiotherapy can occur within about one month, or within about one, two or three weeks, or within about one, two, three, four, five, or six days, of each other.

In some aspects, the subject does not have an increased risk of CRS (e.g., has not experienced Grade 3+ CRS during treatment with a bispecific antibody or CAR-T therapy; does not have detectable circulating plasma cells; and/or does not have extensive extramedullary disease).

/'/. Efficacy

In some aspects, the overall response rate (ORR) for patients treated using the methods described herein is at least 25%, e.g., is at least 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100%. In some aspects, the ORR is at least 40%. In some aspects, the ORR is at least 45% (e.g., at least 45%, 45.5%, 46%, 46.5% 47%, 47.5%, 48%, 48.5%, 49%, 49.5%, or 50%) at least 55%, or at least 65%. In some aspects, the ORR is at least 47.2%. In some aspects, the ORR is about 47.2%. In some aspects, the ORR is 75% or greater. In some aspects, at least 1% of patients (e.g., at least 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%,

30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%,

47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%,

64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%,

81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%,

98%, 99%, or 100% of patients) have a complete response (CR) or a very good partial response (VGPR). In some aspects, the ORR is 40%-50%, and 10%-20% of patients have a CR or a VGPR. In some aspects, the ORR is at least 40%, and at least 20% of patients have a CR or a VGPR. In some aspects, the average duration of response (DoR) for patients treated using the methods described herein is at least two months, e.g., at least three months, at least four months, at least five months, at least six months, at least seven months, at least eight months, at least nine months, at least ten months, at least eleven months, at least one year, or more than one year. In some aspects, the average DoR is at least four months. In some aspects, the average DoR is at least five months. In some aspects, the average DoR is at least seven months.

In some aspects, the six month progression-free survival (PFS) rate for patients treated using the methods described herein is at least 10%, e.g., is at least 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100%. In some aspects, the six month PFS rate is at least 25%. In some aspects, the six month PFS rate is at least 40%. In some aspects, the six month PFS rate is at least 55%.

VI. EXAMPLE

The following is an example of the methods of the invention. It is understood that various other embodiments may be practiced, given the general description provided above, and the example is not intended to limit the scope of the claims.

Example 1. Classifying Subjects with Similarity Network Fusion

The following example describes similarity network fusion (SNF) analysis on data obtained from baseline bone marrow (BM) aspirate samples, baseline peripheral blood samples, and baseline subject information (e.g., clinical data) that was collected from study GO39775 (Clinical Trial Identifier: NCT03275103).

GO39775 (NCT03275103) is an open-label, multicenter, Phase I trial evaluating the safety and pharmacokinetics of escalating doses of the anti-FcRH5/anti-CD3 T-cell-dependent bispecific antibody (TDB) cevostamab (BFCR4350A) in subjects with relapsed or refractory (R/R) multiple myeloma (MM) for whom no established therapy for MM is appropriate and available or who are intolerant to those established therapies.

Cevostamab (BFCR4350A) is a humanized, full-length immunoglobulin (Ig) G1 anti-fragment crystallizable receptor-like 5/cluster of differentiation 3 (anti-FcRH5/anti-CD3) T-cell-dependent bispecific antibody (TDB) (Atwell et al., J Mol Bio, 270: 26-35, 1997; Spiess et al., Nat Biotechnol, 31 (8): 753-758, 2013).

SNF (compbio.cs. toronto.edu/SNF/SNF/Software.html) is a powerful computational method for data integration (e.g., see Wang et al., Nature Methods, 11 :333-337 (2014), which is incorporated herein by reference). SNF combines different types of omic and non-omic data (FIG. 1) for a given set of samples to create a comprehensive view of similar networks within the set of samples. Using datasets for a cohort of subjects, individual subject data (FIG. 2A) and combined subject similarity matrices (FIG. 2B) are used to construct a similarity network (FIG. 2C) for each of the data types and then iteratively integrate (FIG. 2D) these networks into a comprehensively fused similarity network (FIG. 2E). Advantageously, Applicant discovered that the SNF algorithm can capture sample heterogeneity in a population of MM subjects using information collected from baseline sample information and subject clinical data obtained in the GO39775 study.

Four baseline layers of data were obtained from 228 MM subjects enrolled in the GO39775 study: (1 ) flow cytometry (FC) analysis of blood; (2) FC analysis of BM; (3) clinical data; and (4) prior lines of therapy (FIG. 3A). Each subject from GO39775 was selected as long as there was less than 25% missingness in any data layer. To characterize immune cells, samples were profiled at the central laboratory by 8-color flow cytometry. About 135 markers were used in the FC analysis of BM and blood to determine which cell types were present; exemplary markers included cluster of differentiation 4 (CD4), cluster of differentiation 8 (CD8), cluster of differentiation 16 (CD16), cluster of differentiation 19 (CD19), cluster of differentiation 45RA (CD45RA), cluster of differentiation 56 (CD56), human leukocyte antigen-DR isotype (DR), antigen Kiel 67 (Ki67), programmed cell death protein 1 (PD1 ), Granzyme B (GzB), T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT), T cell immunoglobulin and mucin-domain containing- 3 (TIM3), and c-c chemokine receptor type 7 (CCR7) (e.g., see Table 2). The clinical data layer included the level of soluble factors, such as interferon gamma (IFNy) , B-cell mature antigen (BCMA), interleukin 6 (IL-6), and the level of cellular proteins, such as ferretin, lactate dehydrogenase (LDH), myeloma protein (M protein), and flowering locus C (FLC). Cytokine profiling was performed on baseline plasma samples via electrochemiluminescence and digital ELISA. Table 14 provides the mean level (percent) of cell types in the sample, as well as the fold-change of the given clusters, relative to the reference level (e.g., relative to the mean level of the given cell type in the population of 228 MM subjects). Serum BCMA (sBCMA) levels were quantified using hybrid immunoaffinity capture by liquid chromatography with tandem mass spectrometry. Other features of the subject included Number of lines of a prior cancer therapy, the number of lines of a prior proteosome inhibitor (PI) therapy, the number of treatments with a PI, the number of lines of a prior immunomodulator (IMiD) therapy, the number of treatments with an IMiD, the number of lines of a prior anti-BCMA therapy, the number of treatments with an anti-CD38 antibody, the number of lines of a prior anti-BCMA and chimeric antigen receptor T cell (CAR-T) therapy, the number of treatments with and anti-BCMA antibody and a CAR-T therapy, the number of lines of a prior anti-CD38 therapy, the number of treatments with an anti-BCMA bispecific antibody, the number of lines of a prior CAR-T therapy, the number of lines of a prior bispecific antibody therapy, and the number of lines of a prior anti-BCMA bispecific antibody therapy (e.g., see Table 5). Table 15 provides the mean number of given the feature in the subject, as well as the fold-change of given clusters, relative to the mean reference number (e.g., relative to the mean number of the given feature in the population of 228 MM subjects).

The SNF algorithm was applied to these four data layers, wherein subject similarity networks were constructed for each of the data types using pairwise correlation. Each subject’s similarity network was iteratively integrated using a nonlinear combination method, making them more similar with each step, thereby generating an integrated network. Applying SNF to the data layers described above identified three clusters of subjects: Cluster 1 , Cluster 2, and Cluster 3. The level of cell types in Cluster 1 illustrate that the subjects have an active immune profile; the level of cell types in Cluster 2 illustrate that the subjects have an inactive immune profile; and level of cell types in Cluster 3 illustrate that the subjects have a suppressed immune profile (FIG. 3B). Notably, Cluster 1 and Cluster 2 subjects were responsive to (i.e. , benefitted from) treatment with cevostamab (FIG. 4). Cluster 3, however, had a weaker response to cevostamab, suggesting that Cluster 3 subjects are more resistant to treatment with cevostamab. This observation is bolstered by Kaplan-Meier curves illustrating the progression-free survival (PFS) and overall survival (OS) of subjects in Cluster 1 (subjects that responded to cevostamab treatment and had an activated immune profile), Cluster 2 (subjects that responded to cevostamab treatment and had an inactivated immune profile), and Cluster 3 (subjects that responded to cevostamab treatment and had suppressed immune profile) (FIG. 5).

The responder subjects in Cluster 1 and Cluster 2 represented 71% of the SNF-analyzed samples and had significantly longer OS and PFS than Cluster 3. Thus, Cluster 1 and Cluster 2 were next combined and compared to Cluster 3. Kaplan-Meier curves (FIG. 6) show that responders to cevostamab treatment (Clusters 1 and 2) were significantly associated with PFS (P = 0.0022) and OS (P = 0.0021 ) and had a median PFS (129 days (102-259 days)) and median OS (799 days (608-NA)), which was more than twice the median PFS (65 days (433-133days)) and OS (392 days (214-825 days)) than the non-responder cluster (Cluster 3). These data are bolstered by the degree of responsiveness, according to International Myeloma Working Group (IMWG) criteria (Table 13), to cevostamab treatment in responders (Clusters 1 and 2) and non-responders (Cluster 3) (FIGs. 7A- 7B). Furthermore, cluster 3 subjects had poor prognostic clinical variables such as significantly higher lines of therapy and higher ferritin (FIGs. 8A-8B).

Table 13. International Myeloma Working Group (IMWG) uniform response criteria (2016)

BM = bone marrow; CT = computed tomography; FLC = free light chain; M-protein = monoclonal protein; MRI = magnetic resonance imaging; PET = positron emission tomography; PFS = progression-free survival; SPD = sum of the products of diameters.^a Special attention should be given to the emergence of a different M-protein following treatment, especially in the setting of patients having achieved a conventional CR, often related to oligoclonal reconstitution of the immune system. These bands typically disappear over time, and in some studies, have been associated with a better outcome. Also, appearance of IgGk in patients receiving monoclonal antibodies should be differentiated from the therapeutic antibody.^b In some cases it is possible that the original M-protein light-chain isotype is still detected on immunofixation, but the accompanying heavy-chain component has disappeared; this would not be considered a CR even though the heavy-chain component is not detectable, since it is possible that the clone evolved to one that secreted only light chains. Thus, if a patient has IgA lambda myeloma, then to qualify as a CR there should be no IgA detectable on serum or urine immunofixation; if free lambda is detected without IgA, then it must be accompanied by a different heavy-chain isotype (IgG, IgM, etc.). Modified from Durie et al. 2006. Requires two consecutive assessments to be carried out at any time before the institution of any new therapy (Durie et al. 2015).^c Plasmacytoma measurements should be taken from the CT portion of the PET/CT or MRI scans, or dedicated CT scans where applicable. For patients with only skin involvement, the skin lesions should be measured with a ruler. Measurement of tumor size will be determined by the SPD.^d Positive immunofixation alone in a patient previously classified as achieving a CR will not be considered progression. Criteria for relapse from a CR should be used only when calculating disease-free survival.^e In the case where a value is felt to be a spurious result per investigator discretion (e.g. a possible laboratory error), that value will not be considered when determining the lowest value.^f CRAB features = calcium elevation, renal failure, anemia, lytic bone lesions.

Using FC data, SNF identified differential levels of certain cell types present in the BM (FIG. 9 and FIG. 10A-10B, FIG. 16, FIG. 21 , FIG. 22, and FIG. 24A) and/or blood (FIGs. 11-13 and FIG. 20, and FIG. 24B) of subjects in Clusters 1 , 2, and 3. The level of various cell types present in Cluster 1 shows that Cluster 1 subjects had an activated immune profile, as suggested by the high level of CD8+ and CD4+ activated T cells and low level of Treg cells. Notably, terminally differentiated T cells (e.g., TEM cells and TEMRA cells) were high, suggesting a sign of immune exhaustion. The level of various cell types in Cluster 2 shows that Cluster 2 subjects had an inactivated immune profile, as suggested by the low level of CD8+ and CD4+ activated T cells and low level of Treg cells. Notably, TN cells and TEM cells were high. The level of various cell types in Cluster 3 shows that Cluster 3 subjects had a suppressed immune profile, as suggested by the high level of CD8+ activated T cells and high level of Treg cells. Soluble BCMA and IFNy in Clusters 1 , 2, and 3 are shown in FIG. 19.

Using FC data, SNF identified differential levels of certain cell types present in subjects having prior lines of therapy (FIG. 23), such as five (5) lines of prior therapy (FIGs. 14A-14B) or three (3) lines of a prior therapy (FIGs. 15A-15B). Generally, SNF shows that the fewer prior lines of therapy a subject has received, the more likely the subject will respond to treatment with cevostamab. PFS of subjects that had received a specific prior line of therapy (e.g., anti-BCMA therapy or CART therapy) are shown in FIGs. 17A-17C and FIGs. 18A-18B).

Therefore, unsupervised machine learning-based integrative clustering analysis using SNF with baseline samples from multiple immunologic and clinical data types identified three subpopulations (e.g., Cluster 1 , Cluster 2, and Cluster 3) with unique biological and clinical features reflective of the molecular heterogeneity of R/R MM subjects. Interestingly, these immunologically defined clusters also corresponded to clinical outcomes. Cluster 1 had the strongest response to cevostamab (objective response rate = 69%, very good partial response or better = 44%), followed by Cluster 2 (ORR 51 %, >VGPR 29%) and Cluster 3 (ORR 28%, >VGPR 10%). Cluster 1 and Cluster 2 had a strong response to cevostamab treatment. In contrast, Cluster 3 had a relatively weaker response. Cluster 1 and Cluster 2 were significantly associated with PFS (P = 0.004) and OS (P = 0.0042). Cluster 1 had the longest PFS with median PFS (205 days) compared to Cluster 2 (107 days) and Cluster 3 (65 days) and the highest ORR. Subjects in Cluster 1 showed an activated immune microenvironment with a higher proportion of activated T cells, and a lower proportion of regulatory T cells (Tregs) and lower CD8 T cells with triple-positive immune checkpoint markers (%CD8 PD1⁺ TIGIT+ TIM3+) at baseline versus Clusters 2 and 3. Cluster 2 had the best outcome with median OS (1065 days), nearly twice as long as Cluster 1 (608 days) and three times as long as Cluster 3 (392 days). SNF applied to bone marrow samples showed highest activated T cells, lowest level Treg cells, and lower level of CD8+ T cells with triple positive immune checkpoint markers (CD8+PD1 +TIGIT+TIM3+) at baseline prior to cevostamab treatment. Subjects in Cluster 2 had the best OS and were deficient in CD8+ T cells with minimal activated T cells in the bone marrow and a higher proportion of T naive and central memory cells in both BM and blood at baseline. Subjects in Cluster 3 had the lowest ORR and OS and the highest proportion of Treg and CD8+ T cells with triple positive immune checkpoint markers (CD8+PD1 +TIGIT+TIM3+).

With this discovery, future MM subjects can be classified or identified using Cluster 1 , Cluster 2, and Cluster 3 immune profiles, levels of cell types (e.g., cell types set forth in Table 3, 4, 6, 7, 8, and/or 9), and/or features of the subject (e.g., features set forth in Table 5) described in this application. Subjects identified as likely to benefit (or unlikely to benefit) from treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) thus can be appropriately treated, e.g., as described herein.

Table 14. Levels of Cell Types in a Population of Subjects Having MM

Table 15. Features in a Population of Subjects Having MM

Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, the descriptions and examples should not be construed as limiting the scope of the invention. The disclosures of all patent and scientific literature cited herein are expressly incorporated in their entirety by reference.

Claims

WHAT IS CLAIMED IS:

1 . A method of treating a subject having a multiple myeloma (MM), the method comprising administering to the subject a bispecific antibody that binds to Fc receptor-homolog 5 (FcRH5) and cluster of differentiation 3 (CD3), wherein, prior to the administering of the bispecific antibody:

(a) a sample from the subject has been determined to have a decreased level of one or more cell types set forth in Table 3, as compared to a reference level;

(b) a sample from the subject has been determined to have an increased level of one or more cell types set forth in Table 4, as compared to a reference level; and/or

(c) the subject has been determined to have a lower number in one or more of the features set forth in Table 5, as compared to a reference number.

2. The method of claim 1 , wherein:

(a) the sample from the subject has been determined to have a decreased level of one or more cell types set forth in Table 6, as compared to the reference level; and/or

(b) the sample from the subject has been determined to have an increased level of one or more cell types set forth in Table 7, as compared to the reference level.

3. The method of claim 1 , wherein:

(a) the sample from the subject has been determined to have a decreased level of one or more cell types set forth in Table 8, as compared to the reference level; and/or

(b) the sample from the subject has been determined to have an increased level of one or more cell types set forth in Table 9, as compared to the reference level.

4. A method of treating a subject having an MM, the method comprising:

(I) determining:

(a) a level of one or more cell types set forth in Table 3 and/or Table 4 in a sample from the subject; and/or

(b) one or more of the features of the subject set forth in Table 5;

(II) identifying the subject as one who would benefit from a treatment comprising a bispecific antibody that binds to FcRH5 and CD3, wherein:

(a) the sample from the subject has a decreased level of the one or more cell types set forth in Table 3, as compared to a reference level;

(b) the sample from the subject has an increased level of the one or more cell types set forth in Table 4, as compared to a reference level; and/or

(c) the subject has a lower number in one or more of the features set forth in Table 5, as compared to a reference number, thereby identifying the subject as one who would benefit from the treatment comprising the bispecific antibody that binds to FcRH5 and CD3; and (III) administering to the subject the treatment comprising the bispecific antibody that binds to FcRH5 and CD3.

5. The method of claim 4, wherein the method comprises:

(I) determining a level of one or more cell types set forth in Table 6 and/or Table 7 in a sample from the subject; and

(II) identifying the subject as one who would benefit from the treatment comprising the bispecific antibody that binds to FcRH5 and CD3, wherein:

(a) the sample from the subject has a decreased level of one or more cell types set forth in Table 6, as compared to the reference level; and/or

(b) the sample from the subject has an increased level of one or more cell types set forth in Table 7, as compared to the reference level, thereby identifying the subject as one who would benefit from the treatment comprising the bispecific antibody that binds to FcRH5 and CD3.

6. The method of claim 4, wherein the method comprises:

(I) determining a level of one or more cell types set forth in Table 8 and/or Table 9 in a sample from the subject; and

(a) the sample from the subject has a decreased level of one or more cell types set forth in Table 8, as compared to the reference level; and/or

(b) the sample from the subject has an increased level of one or more cell types set forth in Table 9, as compared to the reference level, thereby identifying the subject as one who would benefit from the treatment comprising the bispecific antibody that binds to FcRH5 and CD3.

7. A method of identifying a subject having an MM as one who would benefit from a treatment comprising a bispecific antibody that binds to FcRH5 and CD3, the method comprising:

(I) determining:

(b) one or more of the features set forth in Table 5 of the subject; and

(b) the sample from the subject has an increased level of the one or more cell types set forth in Table 4, as compared to a reference level; and/or (c) the subject has a lower number in one or more of the features set forth in Table 5, as compared to a reference number, thereby identifying the subject as one who would benefit from the treatment comprising the bispecific antibody that binds to FcRH5 and CD3.

8. The method of claim 7, wherein the method comprises:

9. The method of claim 7, wherein the method comprises:

10. The method of any one of claims 7-9, wherein the method further comprises administering to the subject the treatment comprising the bispecific antibody that binds to FcRH5 and CD3.

1 1 . The method of any one of claims 1 , 2, 4, 5, 7, 8, and 10, wherein the sample from the subject is a bone marrow sample.

12. The method of any one of claims 1 , 3, 4, 6, 7, 9, and 10, wherein the sample from the subject is a blood sample.

13. The method of any one of claims 4-12, wherein determining the level of the one or more cell types comprises flow cytometry (FC), mass spectrometry (MS), immunohistochemistry (IHC), DNA sequencing (DNA-seq), RNA sequencing (RNA-seq), quantitative PCR (qPCR), reverse transcription- quantitative polymerase chain reaction (RT-qPCR), multiplex qPCR or RT-qPCR, microarray analysis, serial analysis of gene expression (SAGE), MASSARRAY® technique, in situ hybridization (ISH), or a combination thereof.

14. The method of any one of claims 4-13, wherein determining the level of the one or more cell types comprises FC.

15. The method of any one of claims 1 -14, wherein the reference level is a mean Z-score of the one or more cell types in a population of subjects having the MM.

16. The method of any one of claims 1 -15, wherein the reference number is a mean of the one or more features set forth in Table 5 in a population of subjects of having the MM.

17. The method of any one of claims 4-16, wherein the benefit from the treatment comprises a relative increase in overall survival (OS), objective response rate (ORR), progression-free survival (PFS), complete response (CR), partial response (PR), or a combination thereof.

18. The method of claim 17, wherein the benefit from the treatment comprises a relative increase in OS.

19. The method of any one of claims 1 -18, wherein the MM is a relapsed or refractory (R/R) MM.

20. The method of any one of claims 1 -19, wherein the bispecific antibody that binds to FcRH5 and CD3 comprises an anti-FcRH5 arm comprising a first binding domain comprising the following six hypervariable regions (HVRs):

(a) an HVR-H1 comprising the amino acid sequence of RFGVH (SEQ ID NO: 1 );

(b) an HVR-H2 comprising the amino acid sequence of VIWRGGSTDYNAAFVS (SEQ ID NO: 2);

(c) an HVR-H3 comprising the amino acid sequence of HYYGSSDYALDN (SEQ ID NO:3);

(d) an HVR-L1 comprising the amino acid sequence of KASQDVRNLVV (SEQ ID NO: 4);

(e) an HVR-L2 comprising the amino acid sequence of SGSYRYS (SEQ ID NO: 5); and

(f) an HVR-L3 comprising the amino acid sequence of QQHYSPPYT (SEQ ID NO: 6).

21 . The method of any one of claims 1 -20, wherein the bispecific antibody that binds to FcRH5 and CD3 comprises an anti-FcRH5 arm comprising a first binding domain comprising (a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 7; (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 8; or (c) a VH domain as in (a) and a VL domain as in (b).

22. The method of claim 21 , wherein the first binding domain comprises a VH domain comprising an amino acid sequence of SEQ ID NO: 7 and a VL domain comprising an amino acid sequence of SEQ ID NO: 8.

23. The method of any one of claims 1 -22, wherein the bispecific antibody that binds to FcRH5 and CD3 comprises an anti-CD3 arm comprising a second binding domain comprising the following six HVRs:

(a) an HVR-H1 comprising the amino acid sequence of SYYIH (SEQ ID NO: 9);

(b) an HVR-H2 comprising the amino acid sequence of WIYPENDNTKYNEKFKD (SEQ ID NO: 10);

(c) an HVR-H3 comprising the amino acid sequence of DGYSRYYFDY (SEQ ID NO: 11 );

(d) an HVR-L1 comprising the amino acid sequence of KSSQSLLNSRTRKNYLA (SEQ ID NO: 12);

(e) an HVR-L2 comprising the amino acid sequence of WTSTRKS (SEQ ID NO: 13); and

(f) an HVR-L3 comprising the amino acid sequence of KQSFILRT (SEQ ID NO: 14).

24. The method of any one of claims 1 -23, wherein the bispecific antibody that binds to FcRH5 and CD3 comprises an anti-CD3 arm comprising a second binding domain comprising (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 15; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 16; or (c) a VH domain as in (a) and a VL domain as in (b).

25. The method of claim 24, wherein the second binding domain comprises a VH domain comprising an amino acid sequence of SEQ ID NO: 15 and a VL domain comprising an amino acid sequence of SEQ ID NO: 16.

26. The method of any one of claims 1 -25, wherein the bispecific antibody that binds to FcRH5 and CD3 comprises an anti-FcRH5 arm comprising a heavy chain polypeptide (H1 ) and a light chain polypeptide (L1 ) and an anti-CD3 arm comprising a heavy chain polypeptide (H2) and a light chain polypeptide (L2), and wherein:

(a) H1 comprises the amino acid sequence of SEQ ID NO: 35;

(b) L1 comprises the amino acid sequence of SEQ ID NO: 36;

(c) H2 comprises the amino acid sequence of SEQ ID NO: 37; and

(d) L2 comprises the amino acid sequence of SEQ ID NO: 38.

27. The method of any one of claims 1 -26, wherein the bispecific antibody that binds to FcRH5 and CD3 comprises an aglycosylation site mutation.

28. The method of claim 27, wherein the aglycosylation site mutation reduces effector function of the bispecific antibody.

29. The method of claim 27 or 28, wherein the aglycosylation site mutation is a substitution mutation.

30. The method of claim 29, wherein the bispecific antibody that binds to FcRH5 and CD3 comprises a substitution mutation in the Fc region that reduces effector function.

31 . The method of any one of claims 1 -30, wherein the bispecific antibody that binds to FcRH5 and CD3 is a monoclonal antibody.

32. The method of any one of claims 1 -31 , wherein the bispecific antibody that binds to FcRH5 and CD3 is a chimeric antibody.

33. The method of any one of claims 1 -32, wherein the bispecific antibody that binds to FcRH5 and CD3 is a humanized antibody.

34. The method of any one of claims 1 -25 and 27-33, wherein the bispecific antibody that binds to FcRH5 and CD3 is an antibody fragment.

35. The method of claim 34, wherein the antibody fragment is selected from the group consisting of Fab, Fab’-SH, Fv, scFv, and (Fab’)2 fragments.

36. The method of any one of claims 1 -33, wherein the bispecific antibody that binds to FcRH5 and CD3 is a full-length antibody.

37. The method of any one of claims 1 -33 and 36, wherein the bispecific antibody that binds to FcRH5 and CD3 is an IgG antibody.

38. The method of claim 37, wherein the IgG antibody is an IgG 1 antibody.

39. The method of any one of claims 1 -33 and 36-38, wherein the bispecific antibody that binds to FcRH5 and CD3 comprises one or more heavy chain constant domains, wherein the one or more heavy chain constant domains are selected from a first CH1 (CH11) domain, a first CH2 (CH2i) domain, a first CH3 (CH3i) domain, a second CH1 (CHI 2) domain, second CH2 (CH22) domain, and a second CH3 (CH32) domain.

40. The method of claim 39, wherein at least one of the one or more heavy chain constant domains is paired with another heavy chain constant domain.

41 . The method of claim 39 or 40, wherein the CH3i and CH32 domains each comprise a protuberance or cavity, and wherein the protuberance or cavity in the CH3i domain is positionable in the cavity or protuberance, respectively, in the CH32 domain.

42. The method of claim 41 , wherein the CH3i and CH32 domains meet at an interface between the protuberance and cavity.

43. The method of any one of claims 39-42, wherein the CH2i and CH22 domains each comprise a protuberance or cavity, and wherein the protuberance or cavity in the CH2i domain is positionable in the cavity or protuberance, respectively, in the CH22 domain.

44. The method of claim 43, wherein the CH2i and CH22 domains meet at an interface between said protuberance and cavity.

45. The method of claim 42, wherein the anti-FcRH5 arm comprises the protuberance and the anti- CD3 arm comprises the cavity.

46. The method of claim 45, wherein the anti-FcRH5 arm comprises a protuberance comprising a T366W amino acid substitution mutation (EU numbering) and the anti-CD3 arm comprises a cavity comprising T366S, L368A, and Y407V amino acid substitution mutations (EU numbering).

47. The method of any one of claims 1 -33 and 36-46, wherein the bispecific antibody that binds to FcRH5 and CD3 is cevostamab.

48. The method of any one of claims 1 -47, wherein the bispecific antibody that binds to FcRH5 and CD3 is administered to the subject as a monotherapy.

49. The method of any one of claims 1 -47, wherein the bispecific antibody that binds to FcRH5 and CD3 is administered to the subject as a combination therapy.

50. The method of claim 49, wherein the bispecific antibody that binds to FcRH5 and CD3 is administered to the subject concurrently with one or more additional therapeutic agents.

51 . The method of claim 49, wherein the bispecific antibody that binds to FcRH5 and CD3 is administered to the subject prior to the administration of one or more additional therapeutic agents.

52. The method of claim 49, wherein the bispecific antibody that binds to FcRH5 and CD3 is administered to the subject subsequent to the administration of one or more additional therapeutic agents.

53. The method of claim 52, wherein the one or more additional therapeutic agents comprise an effective amount of tocilizumab.

54. The method of claim 53, wherein tocilizumab is administered to the subject by intravenous infusion.

55. The method of claim 53 or 54, wherein:

(a) the subject weighs > 100 kg, and tocilizumab is administered to the subject at a dose of 800 mg;

(b) the subject weighs > 30 kg and < 100 kg, and tocilizumab is administered to the subject at a dose of 8 mg/kg; or

(c) the subject weighs < 30 kg, and tocilizumab is administered to the subject at a dose of 12 mg/kg.

56. The method of any one of claims 53-55, wherein tocilizumab is administered to the subject 2 hours before administration of the bispecific antibody.

57. The method of any one of claims 50-52, wherein the one or more additional therapeutic agents comprises an effective amount of a corticosteroid, an analgesic and antipyretic, an antihistamine, an anti-myeloma agent, a PD-1 axis binding antagonist, an anti-CD38 therapeutic agent, an immunomodulatory (IMiD) agent, a cereblon E3 ligase modulatory drug (CELMoD), a proteosome inhibitor (PI), a CAR-T therapy, an anti-neoplastic agent, a chemotherapeutic agent, a growth inhibitory agent, an anti-angiogenic agent, a radiation therapy, a cytotoxic agent, a cell-based therapy, or a combination thereof.

58. The method of any one of claims 1 -57, wherein the bispecific antibody that binds to FcRH5 and CD3 is administered to the subject by intravenous infusion.

59. The method of any one of claims 1 -57, wherein the bispecific antibody that binds to FcRH5 and CD3 is administered to the subject subcutaneously.

60. The method of any one of claims 1 -59, wherein the subject has a cytokine release syndrome (CRS) event, and the method further comprises treating the symptoms of the CRS event while suspending treatment with the bispecific antibody that binds to FcRH5 and CD3.

61 . The method of claim 60, wherein the method further comprises administering to the subject an effective amount of tocilizumab to treat the CRS event.

62. The method of claim 61 , wherein tocilizumab is administered intravenously to the subject as a single dose of about 8 mg/kg.

63. The method of claim 61 or 62, wherein the CRS event does not resolve or worsens within 24 hours of treating the symptoms of the CRS event, the method further comprising administering to the subject one or more additional doses of tocilizumab to manage the CRS event.

64. The method of claim 63, wherein the one or more additional doses of tocilizumab are administered intravenously to the subject at a dose of about 8 mg/kg.

65. A method of classifying an MM in a subject, the method comprising:

(I) determining a level of CD8+ T cells, Treg cells, and CD8+ TN cells in a sample from the subject, and

(II) assigning the subject’s MM to one of the following immune profiles based on the level of the CD8+ T cells, Treg cells, and CD8+ TN cells:

(a) an activated immune profile;

(b) an inactivated immune profile; or

(c) a suppressed immune profile, thereby classifying the MM in the subject.

66. The method of claim 65, wherein:

(I) the activated immune profile comprises:

(a) an increased level of CD8+ T cells;

(b) a decreased level of Treg cells; and

(c) a decreased level of CD8+ TN cells, in the sample from the subject, as compared to a reference level ;(ll) the inactivated immune profile comprises:

(a) a decreased level of CD8+ T cells;

(b) an increased level of Treg cells; and

(c) an increased level of CD8+ TN cells, in the sample from the subject, as compared to a reference level; or

(III) the suppressed immune profile comprises: (a) an increased level of CD8+ T cells;

(b) an increased level of Treg cells; and

(c) a decreased level of CD8+ TN cells, in the sample from the subject, as compared to a reference level.

67. The method of claim 65 or 66, wherein the immune profile is assigned by a similarity network fusion (SNF) analysis.

68. A bispecific antibody that binds to FcRH5 and CD3 for use in a treatment of a subject having an MM, wherein prior to an administration of the bispecific antibody:

(a) a sample from the subject has been determined to have a decreased level of one or more cell types set forth in Table 1 , as compared to a reference level;

(b) a sample from the subject has been determined to have an increased level of one or more cell types set forth in Table 2, as compared to a reference level; and/or

(c) the subject has been determined to have a lower number in one or more of the features set forth in Table 3, as compared to a reference number.

69. The bispecific antibody that binds to FcRH5 and CD3 for use of claim 68, wherein:

(a) the sample from the subject has been determined to have a decreased level of one or more cell types set forth in Table 4, as compared to the reference level; and/or

(b) the sample from the subject has been determined to have an increased level of one or more cell types set forth in Table 5, as compared to the reference level.

70. The bispecific antibody that binds to FcRH5 and CD3 for use of claim 68, wherein:

71 . A bispecific antibody that binds to FcRH5 and CD3 for use in a treatment of a subject having an MM, the treatment comprising:

(I) determining:

(a) a level of one or more cell types set forth in Table 1 and/or Table 2 in a sample from the subject; and/or

(b) one or more of the features of the subject set forth in Table 3;

(a) the sample from the subject has a decreased level of the one or more cell types set forth in Table 1 , as compared to a reference level; (b) the sample from the subject has an increased level of the one or more cell types set forth in Table 2, as compared to a reference level; and/or

(c) the subject has a lower number in one or more of the features set forth in Table 3, as compared to a reference number, thereby identifying the subject as one who would benefit from the treatment comprising the bispecific antibody that binds to FcRH5 and CD3; and

(III) administering to the subject the treatment comprising the bispecific antibody that binds to FcRH5 and CD3.

72. The bispecific antibody that binds to FcRH5 and CD3 for use of claim 71 , wherein the treatment comprises:

(I) determining a level of one or more cell types set forth in Table 4 and/or Table 5 in a sample from the subject; and

(a) the sample from the subject has a decreased level of one or more cell types set forth in Table 4, as compared to the reference level; and/or

(b) the sample from the subject has an increased level of one or more cell types set forth in Table 5, as compared to the reference level, thereby identifying the subject as one who would benefit from the treatment comprising the bispecific antibody that binds to FcRH5 and CD3.

73. The bispecific antibody that binds to FcRH5 and CD3 for use of claim 71 , wherein the treatment comprises:

74. A bispecific antibody that binds to FcRH5 and CD3 for use in a method of identifying a subject having an MM as one who would benefit from a treatment comprising the bispecific antibody that binds to FcRH5 and CD3, the method comprising:

(I) determining: (a) a level of one or more cell types set forth in Table 1 and/or Table 2 in a sample from the subject; and/or

(b) one or more of the features set forth in Table 3 of the subject; and

(a) the sample from the subject has a decreased level of the one or more cell types set forth in Table 1 , as compared to a reference level;

(b) the sample from the subject has an increased level of the one or more cell types set forth in Table 2, as compared to a reference level; and/or

(c) the subject has a lower number in one or more of the features set forth in Table 3, as compared to a reference number, thereby identifying the subject as one who would benefit from the treatment comprising the bispecific antibody that binds to FcRH5 and CD3.

75. The bispecific antibody that binds to FcRH5 and CD3 for use of claim 74, wherein the method comprises:

76. The bispecific antibody that binds to FcRH5 and CD3 for use of claim 74, wherein the method comprises:

77. The bispecific antibody that binds to FcRH5 and CD3 for use of any one of claims 74-76, wherein the method further comprises administering to the subject the treatment comprising the bispecific antibody that binds to FcRH5 and CD3.

78. A bispecific antibody that binds to FcRH5 and CD3 for use in treatment of a subject having an MM, the treatment comprising a step of classifying the subject, the step of classifying comprising:

(a) an activated immune profile;

(b) an inactivated immune profile; or

(c) a suppressed immune profile, thereby classifying the MM in the subject.

79. The bispecific antibody that binds to FcRH5 and CD3 for use of claim 78, wherein:

(I) the activated immune profile comprises:

(a) an increased level of CD8+ T cells;

(b) a decreased level of Treg cells; and

(a) a decreased level of CD8+ T cells;

(b) an increased level of Treg cells; and

(III) the suppressed immune profile comprises:

(a) an increased level of CD8+ T cells;

(b) an increased level of Treg cells; and

80. The bispecific antibody that binds to FcRH5 and CD3 for use of claim 78 or 79, wherein the immune profile is assigned by SNF.

81 . The bispecific antibody that binds to FcRH5 and CD3 for use of any one of claims 68, 69, 71 , 72, 74, 75, and 77-80, wherein the sample form the subject is a bone marrow sample.

82. The bispecific antibody that binds to FcRH5 and CD3 for use of any one of claims 68, 69, 71 , 72, 74, 75, and 77-80, wherein the sample form the subject is a blood sample.

83. The bispecific antibody that binds to FcRH5 and CD3 for use of any one of claims 69-82, wherein determining the level of the one or more cell types comprises flow cytometry (FC), mass spectrometry (MS), immunohistochemistry (IHC), DNA sequencing (DNA-seq), RNA sequencing (RNA-seq), quantitative PCR (qPCR), reverse transcription-quantitative polymerase chain reaction (RT-qPCR), multiplex qPCR or RT-qPCR, microarray analysis, serial analysis of gene expression (SAGE), MASSARRAY® technique, in situ hybridization (ISH), or a combination thereof.

84. The bispecific antibody that binds to FcRH5 and CD3 for use of any one of claims 71 -83, wherein determining the level of the one or more cell types comprises FC.

85. The bispecific antibody that binds to FcRH5 and CD3 for use of any one of claims 68-84, wherein the reference level is a mean Z-score of the one or more cell types in a population of subjects having the MM.

86. The bispecific antibody that binds to FcRH5 and CD3 for use of any one of claims 68-85, wherein the reference number is a mean of the one or more features set forth in Table 3 in a population of subjects of having the MM.

87. The bispecific antibody that binds to FcRH5 and CD3 for use of any one of claims 71 -86, wherein the benefit from the treatment comprises a relative increase in overall survival (OS), objective response rate (ORR), progression-free survival (PFS), complete response (CR), partial response (PR), or a combination thereof.

88. The bispecific antibody that binds to FcRH5 and CD3 for use of claim 87, wherein the benefit from the treatment comprises a relative increase in OS.

89. The bispecific antibody that binds to FcRH5 and CD3 for use of any one of claims 68-88, wherein the MM is a relapsed or refractory (R/R) MM.

90. The bispecific antibody that binds to FcRH5 and CD3 for use of any one of claims 68-89, wherein the bispecific antibody that binds to FcRH5 and CD3 comprises an anti-FcRH5 arm comprising a first binding domain comprising the following six hypervariable regions (HVRs):

(a) an HVR-H1 comprising the amino acid sequence of RFGVH (SEQ ID NO: 1 );

(c) an HVR-H3 comprising the amino acid sequence of HYYGSSDYALDN (SEQ ID NO:3); (d) an HVR-L1 comprising the amino acid sequence of KASQDVRNLVV (SEQ ID NO: 4);

(e) an HVR-L2 comprising the amino acid sequence of SGSYRYS (SEQ ID NO: 5); and

(f) an HVR-L3 comprising the amino acid sequence of QQHYSPPYT (SEQ ID NO: 6).

91 . The bispecific antibody that binds to FcRH5 and CD3 for use of any one of claims 68-90, wherein the bispecific antibody that binds to FcRH5 and CD3 comprises an anti-FcRH5 arm comprising a first binding domain comprising (a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 7; (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 8; or (c) a VH domain as in (a) and a VL domain as in (b).

92. The bispecific antibody that binds to FcRH5 and CD3 for use of claim 91 , wherein the first binding domain comprises a VH domain comprising an amino acid sequence of SEQ ID NO: 7 and a VL domain comprising an amino acid sequence of SEQ ID NO: 8.

93. The bispecific antibody that binds to FcRH5 and CD3 for use of any one of claims 68-92, wherein the bispecific antibody that binds to FcRH5 and CD3 comprises an anti-CD3 arm comprising a second binding domain comprising the following six HVRs:

(a) an HVR-H1 comprising the amino acid sequence of SYYIH (SEQ ID NO: 9);

(f) an HVR-L3 comprising the amino acid sequence of KQSFILRT (SEQ ID NO: 14).

94. The bispecific antibody that binds to FcRH5 and CD3 for use of any one of claims 68-93, wherein the bispecific antibody that binds to FcRH5 and CD3 comprises an anti-CD3 arm comprising a second binding domain comprising (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 15; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 16; or (c) a VH domain as in (a) and a VL domain as in (b).

95. The bispecific antibody that binds to FcRH5 and CD3 for use of claim 94, wherein the second binding domain comprises a VH domain comprising an amino acid sequence of SEQ ID NO: 15 and a VL domain comprising an amino acid sequence of SEQ ID NO: 16.

96. The bispecific antibody that binds to FcRH5 and CD3 for use of any one of claims 68-95, wherein the bispecific antibody that binds to FcRH5 and CD3 comprises an anti-FcRH5 arm comprising a heavy chain polypeptide (H1 ) and a light chain polypeptide (L1 ) and an anti-CD3 arm comprising a heavy chain polypeptide (H2) and a light chain polypeptide (L2), and wherein:

(a) H1 comprises the amino acid sequence of SEQ ID NO: 35;

(b) L1 comprises the amino acid sequence of SEQ ID NO: 36;

(c) H2 comprises the amino acid sequence of SEQ ID NO: 37; and

(d) L2 comprises the amino acid sequence of SEQ ID NO: 38.

97. The bispecific antibody that binds to FcRH5 and CD3 for use of any one of claims 68-96, wherein the bispecific antibody that binds to FcRH5 and CD3 comprises an aglycosylation site mutation.

98. The bispecific antibody that binds to FcRH5 and CD3 for use of claim 97, wherein the aglycosylation site mutation reduces effector function of the bispecific antibody.

99. The bispecific antibody that binds to FcRH5 and CD3 for use of claim 97 or 98, wherein the aglycosylation site mutation is a substitution mutation.

100. The bispecific antibody that binds to FcRH5 and CD3 for use of claim 99, wherein the bispecific antibody that binds to FcRH5 and CD3 comprises a substitution mutation in the Fc region that reduces effector function.

101 . The bispecific antibody that binds to FcRH5 and CD3 for use of any one of claims 68-100, wherein the bispecific antibody that binds to FcRH5 and CD3 is a monoclonal antibody.

102. The bispecific antibody that binds to FcRH5 and CD3 for use of any one of claims 68-101 , wherein the bispecific antibody that binds to FcRH5 and CD3 is a chimeric antibody.

103. The bispecific antibody that binds to FcRH5 and CD3 for use of any one of claims 68-102, wherein the bispecific antibody that binds to FcRH5 and CD3 is a humanized antibody.

104. The bispecific antibody that binds to FcRH5 and CD3 for use of any one of claims 68-95 and 97- 103, wherein the bispecific antibody that binds to FcRH5 and CD3 is an antibody fragment.

105. The bispecific antibody that binds to FcRH5 and CD3 for use of claim 104, wherein the antibody fragment is selected from the group consisting of Fab, Fab’-SH, Fv, scFv, and (Fab’)2 fragments.

106. The bispecific antibody that binds to FcRH5 and CD3 for use of any one of claims 68-103, wherein the bispecific antibody that binds to FcRH5 and CD3 is a full-length antibody.

107. The bispecific antibody that binds to FcRH5 and CD3 for use of any one of claims 68-103 and 106, wherein the bispecific antibody that binds to FcRH5 and CD3 is an IgG antibody.

108. The bispecific antibody that binds to FcRH5 and CD3 for use of claim 107, wherein the IgG antibody is an IgG 1 antibody.

109. The bispecific antibody that binds to FcRH5 and CD3 for use of any one of claims 68-103 and

106-108, wherein the bispecific antibody that binds to FcRH5 and CD3 comprises one or more heavy chain constant domains, wherein the one or more heavy chain constant domains are selected from a first CH1 (CH1 j) domain, a first CH2 (CH2j) domain, a first CH3 (CH3y) domain, a second CH1 (CH1₂) domain, second CH2 (CH2₂) domain, and a second CH3 (CH3₂) domain.

110. The bispecific antibody that binds to FcRH5 and CD3 for use of claim 109, wherein at least one of the one or more heavy chain constant domains is paired with another heavy chain constant domain.

111. The bispecific antibody that binds to FcRH5 and CD3 for use of claim 109 or 110, wherein the CH3y and CH3₂ domains each comprise a protuberance or cavity, and wherein the protuberance or cavity in the CH3y domain is positionable in the cavity or protuberance, respectively, in the CH3₂ domain.

112. The bispecific antibody that binds to FcRH5 and CD3 for use of claim 111 , wherein the CH3j and CH3₂ domains meet at an interface between the protuberance and cavity.

113. The bispecific antibody that binds to FcRH5 and CD3 for use of any one of claims 109-112, wherein the CH2j and CH2₂ domains each comprise a protuberance or cavity, and wherein the protuberance or cavity in the CH2j domain is positionable in the cavity or protuberance, respectively, in the CH2₂ domain.

114. The bispecific antibody that binds to FcRH5 and CD3 for use of claim 113, wherein the CH2j and CH2₂ domains meet at an interface between said protuberance and cavity.

115. The bispecific antibody that binds to FcRH5 and CD3 for use of claim 112, wherein the anti- FcRH5 arm comprises the protuberance and the anti-CD3 arm comprises the cavity.

116. The bispecific antibody that binds to FcRH5 and CD3 for use of claim 115, wherein the anti- FcRH5 arm comprises a protuberance comprising a T366W amino acid substitution mutation (EU numbering) and the anti-CD3 arm comprises a cavity comprising T366S, L368A, and Y407V amino acid substitution mutations (EU numbering).

117. The bispecific antibody that binds to FcRH5 and CD3 for use of any one of claims 68-103 and 106-116, wherein the bispecific antibody that binds to FcRH5 and CD3 is cevostamab.

118. The bispecific antibody that binds to FcRH5 and CD3 for use of any one of claims 68-117, wherein the bispecific antibody that binds to FcRH5 and CD3 is formulated for administration to the subject as a monotherapy.

119. The bispecific antibody that binds to FcRH5 and CD3 for use of any one of claims 68-117, wherein the bispecific antibody that binds to FcRH5 and CD3 is formulated for administration to the subject as a combination therapy.

120. The bispecific antibody that binds to FcRH5 and CD3 for use of claim 119, wherein the bispecific antibody that binds to FcRH5 and CD3 is formulated to be administered concurrently with one or more additional therapeutic agents to the subject.

121 . The bispecific antibody that binds to FcRH5 and CD3 for use of claim 119, wherein the bispecific antibody that binds to FcRH5 and CD3 is formulated to be administered to the subject prior to the administration of one or more additional therapeutic agents.

122. The bispecific antibody that binds to FcRH5 and CD3 for use of claim 119, wherein the bispecific antibody that binds to FcRH5 and CD3 is formulated to be administered to the subject subsequent to the administration of one or more additional therapeutic agents.

123. The bispecific antibody that binds to FcRH5 and CD3 for use of claim 122, wherein the one or more additional therapeutic agents comprise an effective amount of tocilizumab.

124. The bispecific antibody that binds to FcRH5 and CD3 for use of claim 123, wherein tocilizumab is administered to the subject by intravenous infusion.

125. The bispecific antibody that binds to FcRH5 and CD3 for use of claim 123 or 124, wherein:

126. The bispecific antibody that binds to FcRH5 and CD3 for use of any one of claims 123-125, wherein tocilizumab is administered to the subject 2 hours before administration of the bispecific antibody.

127. The bispecific antibody that binds to FcRH5 and CD3 for use of any one of claims 120-122, wherein the one or more additional therapeutic agents comprises an effective amount of a corticosteroid, an analgesic and antipyretic, an antihistamine, an anti-myeloma agent, a PD-1 axis binding antagonist, an anti-CD38 therapeutic agent, an immunomodulatory (IMiD) agent, a cereblon E3 ligase modulatory drug (CELMoD), a proteosome inhibitor (PI), a CAR-T therapy, an anti- neoplastic agent, a chemotherapeutic agent, a growth inhibitory agent, an anti-angiogenic agent, a radiation therapy, a cytotoxic agent, a cell-based therapy, or a combination thereof.

128. The bispecific antibody that binds to FcRH5 and CD3 for use of any one of claims 68-127, wherein the bispecific antibody that binds to FcRH5 and CD3 is formulated for administration by intravenous infusion to the subject.

129. The bispecific antibody that binds to FcRH5 and CD3 for use of any one of claims 68-127, wherein the bispecific antibody that binds to FcRH5 and CD3 is formulated for subcutaneous administration to the subject.

130. The bispecific antibody that binds to FcRH5 and CD3 for use of any one of claims 68-129, wherein the subject has a cytokine release syndrome (CRS) event, and the method further comprises treating the symptoms of the CRS event while suspending treatment with the bispecific antibody that binds to FcRH5 and CD3.

131 . The bispecific antibody that binds to FcRH5 and CD3 for use of claim 130, wherein the method further comprises administering to the subject an effective amount of tocilizumab to treat the CRS event.

132. The bispecific antibody that binds to FcRH5 and CD3 for use of claim 131 , wherein tocilizumab is administered intravenously to the subject as a single dose of about 8 mg/kg.

133. The bispecific antibody that binds to FcRH5 and CD3 for use of claim 131 or 132, wherein the CRS event does not resolve or worsens within 24 hours of treating the symptoms of the CRS event, the method further comprising administering to the subject one or more additional doses of tocilizumab to manage the CRS event.

134. The bispecific antibody that binds to FcRH5 and CD3 for use of claim 133, wherein the one or more additional doses of tocilizumab are administered intravenously to the subject at a dose of about 8 mg/kg.